Abuse deterrent pharmaceutical compositions for controlled release

ABSTRACT

The present disclosure relates to pharmaceutical compositions that are abuse resistant and may also provide controlled release. The present disclosure also relates to the use of pharmaceutical compositions in the treatment of pain.

All patent and non-patent references cited in the application are herebyincorporated by reference in their entirety.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/668,741, filed on Jul. 6, 2012, the contents of which areincorporated herein by reference.

FIELD OF INVENTION

The present disclosure relates to pharmaceutical compositions. Incertain embodiments, the pharmaceutical compositions according to thepresent description are abuse-deterrent and may provide controlledrelease.

BACKGROUND OF INVENTION

Increased attention has been drawn to the abuse of prescriptionpharmaceutical compositions. The abuse, or non-medicinal use, ofprescription pharmaceutical compositions has been reported to be anincreasing problem. In North America, abuse of prescriptionpharmaceutical compositions has become an important issue for the U.S.Food and Drug Administration (FDA), and the pharmaceutical industry isstriving to develop abuse-deterrent pharmaceutical compositions in orderto reduce the potential for misuse of prescription pharmaceuticalcompositions. Prescription pharmaceutical compositions that aretypically misused fall, primarily, into three groups: 1) Opioidsprescribed for pain; 2) Central Nervous System (CNS) depressantsprescribed for anxiety or sleep problems; and 3) Stimulants, prescribed,for example, for attention deficit hyperactivity, narcolepsy, orobesity.

Methods for abusing prescription pharmaceutical compositions are variedand can include, for example, extraction, melting, volatilization,physical tampering (e.g., grinding, grating, crushing, etc.), or directadministration. For purposes of abuse, methods of administering activedrug substances obtained from prescription pharmaceutical compositionsor of the pharmaceutical compositions themselves are similarly diverseand include, for example, injection, smoking, snorting, swallowing,sublingual or buccal administration, chewing, and administration assuppository. Alcohol-induced dose dumping of active drug substance fromprescription pharmaceutical compositions also presents potential abuseand safety problems.

DESCRIPTION OF DRAWINGS

FIG. 1 shows a drawing of a Moulinex-1411R coffee grinder chamber withstainless steel blades.

FIG. 2 shows a drawing of a Krups F203 coffee grinder chamber withstainless steel blades.

FIG. 3 shows a drawing of a nutmeg grater surface with a stainless steelstar blade.

FIG. 4 shows in vitro dissolution results of the release of morphine (%)versus time (minutes) in phosphate buffer solution pH 6.8. The releaseof morphine is shown for intact tablets (untampered) and ground tablets(tampered) of one embodiment of a pharmaceutical composition, asdisclosed herein, comprising PEO 400,000 daltons.

FIG. 5 shows particle size reduction results of one embodiment of aground (tampered) pharmaceutical composition, as disclosed herein,comprising PEO 400,000 daltons.

FIG. 6 shows in vitro dissolution results of the release of oxycodone(%) versus time (minutes) in phosphate buffer solution pH 6.8 with andwithout 40% v/v ethanol. The release of oxycodone is shown for intacttablets (untampered) and ground tablets (tampered) of one embodiment ofa pharmaceutical composition, as disclosed herein, comprising PEO600,000 daltons.

FIG. 7 shows particle size reduction results of one embodiment of aground (tampered) pharmaceutical composition as disclosed hereincomprising PEO 600,000 daltons.

FIG. 8 shows in vitro dissolution results of the release ofhydromorphone (%) versus time (minutes) in phosphate buffer solution pH6.8. The release of hydromorphone is shown for intact tablets(untampered) and ground tablets (tampered) of one embodiment of apharmaceutical composition, as disclosed herein, comprising PEO2,000,000 daltons.

FIG. 9 shows particle size reduction results of one embodiment of aground (tampered) pharmaceutical composition, as disclosed herein,comprising PEO 2,000,000 daltons.

FIG. 10 shows in vitro dissolution results of the release of oxymorphone(%) versus time (minutes) in phosphate buffer solution pH 6.8. Therelease of oxymorphone is shown for intact tablets (untampered) andground tablets (tampered) of one embodiment of a pharmaceuticalcomposition as disclosed herein comprising PEO 10,000,000 daltons.

FIG. 11 shows particle size reduction results of one embodiment of aground (tampered) pharmaceutical composition as disclosed hereincomprising PEO 10,000,000 daltons.

FIG. 12 shows in vitro dissolution results of the release of oxycodone(%) versus time (minutes) in phosphate buffer solution pH 6.8. Therelease of oxycodone is shown for intact tablets (untampered) and groundtablets (tampered) of Oxycontin® OP 40 mg.

FIG. 13 shows particle size reduction results of a ground Oxycontin® OP40 mg tablet.

FIG. 14 shows in vitro dissolution results of the release of morphine(%) versus time (minutes) in phosphate buffer solution pH 6.8 with andwithout 40% v/v ethanol. The release of morphine is shown for intacttablets of one embodiment of a pharmaceutical composition, as disclosedherein.

FIG. 15 shows in vitro dissolution results of release of activesubstance (%) versus time (minutes) in phosphate buffer solution pH 6.8.The release of active substance is shown for intact tablets and groundtablets (ground in a Krups F203 coffee grinder) of Oxycontin® OP 40 mg,MST Continus® 60 mg, and an embodiment of a pharmaceutical composition,as disclosed herein, containing 200 mg of morphine.

FIG. 16 shows in vitro dissolution results of release of activesubstance (%) versus time (minutes) in dilute hydrochloric acid. Therelease of active substance is shown for grated tablets (Nutmeg grater)of Opana® ER 40 mg, Oxycontin® OP 80 mg, MST Continus® 60 mg, and anembodiment of a pharmaceutical composition, as disclosed herein,containing 200 mg of morphine.

FIG. 17 shows particle size reduction results of a grated tablet of anembodiment of a pharmaceutical composition, as disclosed herein,containing 200 mg of morphine.

FIG. 18 shows particle size reduction results of a grated MST Continus®60 mg tablet.

FIG. 19 shows particle size reduction results of a grated Opana® ER 40mg tablet.

FIG. 20 shows particle size reduction results of a grated Oxycontin® OP80 mg tablet.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides novel abuse-deterrent pharmaceuticalcompositions, which are resistant to abuse and tampering. In certainembodiments, the pharmaceutical compositions according to the presentdescription, even without containing an outer shell, exhibit hardnessthat is resistant to physical tampering. In particular embodiments, thepharmaceutical compositions disclosed herein may be formulated in such away that the composition maintains a desired release profile of theactive drug substance, even if the pharmaceutical composition issubjected to physical tampering.

One embodiment of the present disclosure provides an abuse-deterrentpharmaceutical composition, comprising: (a) an active drug substance;(b) a polyethylene oxide; and (c) optionally, a plasticizer, wherein thepharmaceutical composition does not provide immediate release of theactive drug substance after physical tampering, and wherein when atleast one polyethylene oxide has a molecular weight of at least1,000,000 daltons, then the pharmaceutical composition comprises atleast 5% w/w plasticizer.

In particular embodiments, the pharmaceutical compositions disclosedherein may comprise a controlled released abuse-deterrent pharmaceuticalcomposition with a route of administration that may prevent or limit thefeeling of euphoria combined with preventing or making it more difficultto abuse the active drug substance from the composition by, for example,injection, smoking, snorting, swallowing, sublingual or buccaladministration, chewing, and administration as suppository.

The abuse-deterrent pharmaceutical compositions according to the presentdescription can be further understood when studied relative to acomparator. Comparison of the abuse-deterrent pharmaceuticalcompositions disclosed herein to a comparator assesses the incrementaland meaningful improvement in the ability of said pharmaceuticalcompositions to deter abuse or misuse.

In addition, certain embodiments of the present disclosure relate to theuse of the disclosed pharmaceutical compositions in the treatment of aclinical condition (such as pain) in an individual in need thereof.

Definitions

For purposes of the present disclosure, “dose dumping” refers to anunintended, rapid release of the entire amount or a significant fractionof the active drug substance contained within a prescriptionpharmaceutical composition over a short or accelerated period of time.For purposes of abuse, alcohol-induced dose dumping may facilitateisolation or concentration of active drug substances from a prescriptionpharmaceutical composition. Alternatively, dose dumping in the presenceof alcohol may increase the ease with which a prescriptionpharmaceutical composition can be abused simply through the intake of analcoholic beverage concomitantly with the prescription pharmaceuticalcomposition. Moreover, alcohol-induced dose dumping may present safetyissues outside the context of abuse. For example, a patient taking aprescription pharmaceutical composition for medicinal purposes mayinadvertently cause delivery of a dose of active drug substance that istoo high or absorbed too quickly by self-administering a pharmaceuticalcomposition shortly before, simultaneously with, or shortly after,consumption or intake of an alcoholic beverage or another pharmaceuticalcomposition containing alcohol (e.g., an over-the-counter cold or flumedicine).

The term “physical tampering,” as used herein, refers to any kind ofphysical interference or manipulation that may result in particle sizereduction of a pharmaceutical composition. Hence, compositions that areresistant to physical tampering are formulated in such a way that thecomposition cannot readily be size reduced to a form that is suitablefor abuse, such as, for example, injection or snorting, because thetablet cannot easily be ground, grated, dissolved, and the like.Examples of physical tampering include, but are not limited to,crushing, grinding, grating, cutting, crisping, and other methods ofparticle size reduction.

The term “controlled release,” as used herein, denotes pharmaceuticalcomposition that provide extended release of an active drug substancefrom the composition for an extended period of time. In certaincircumstances, the term “controlled release” is used to designate arelease at a desired rate during a predetermined release period.Additional or alternative terms, such as, for example, “modified”,“delayed”, “sustained”, “prolonged”, “extended” release may be used, incertain embodiments, as synonyms to the term “controlled release.”

The term “immediate release,” as used herein, denotes a pharmaceuticalcomposition that releases the active drug substance (80% release) withinat the most 30 minutes, when subjected to dissolution test according toUSP 35, NF 30, (711), Apparatus 2.

Polyethylene Oxide

The pharmaceutical compositions of the present disclosure comprise apolyethylene oxide. Polyethylene oxides (PEOs) are linear polydispersenonionic polymers composed of repeating units of ethylene oxide. Theirchemical formula is HO[CH₂CH₂O]_(n)H, where n represents the averagenumber of oxyethylene groups. See the structural presentation ofpolyethylene oxide below, wherein n is the average number of oxyethylenegroups. Depending on preparation method, high molecular weight PEO mayhave one terminal methyl group.

Polyethylene oxides that are suitable for use in the pharmaceuticalcompositions according to the present description are those having anaverage molecular weight of at least about 200,000 daltons, such as anaverage molecular weight of in the range of about 200,000 to about10,000,000 daltons, for example in the range of about 250,000 to about10,000,000 daltons, such as in the range of about 300,000 to about10,000,000 daltons, for example in the range of about 350,000 to about10,000,000 daltons, such as in the range of about 400,000 to about10,000,000 daltons. In certain embodiments, the polyethylene oxides thatare suitable for use in the compositions disclosed herein are thosehaving an average molecular weight of at the most 1,000,000 daltons,such as an average molecular weight of in the range of about 200,000 toabout 1,000,000 daltons, for example in the range of about 300,000 toabout 1,000,000 daltons, such as in the range of about 400,000 to about1,000,000 daltons. In another embodiment, the polyethylene oxides thatare suitable for use in the compositions disclosed herein are thosehaving an average molecular weight of at the most 500,000 daltons, suchas an average molecular weight of in the range of about 200,000 to about500,000 daltons, for example in the range of about 250,000 to about500,000 daltons, such as in the range of about 300,000 to about 500,000daltons, for example in the range of about 350,000 to about 500,000daltons, such as in the range of about 400,000 to about 500,000 daltons.In yet another embodiment, the polyethylene oxides suitable for use inthe compositions described herein are those having an average molecularweight of at the most 400,000 daltons, such as in the range of about100,000 to about 400,000 daltons, for example in the range of about200,000 to about 400,000 daltons, such as in the range of about 300,000to 400,000 daltons. In one embodiment, the pharmaceutical compositioncomprises polyethylene oxides having an average molecular weight of400,000 daltons.

In certain embodiments, the polyethylene oxides suitable for use in thecompositions described herein are those having an average molecularweight selected from 200,000 daltons, 250,000 daltons, 300,000 daltons,350,000 daltons, 400,000 daltons, 450,000 daltons, 500,000 daltons,550,000 daltons, 600,000 daltons, 650,000 daltons, 700,000 daltons,750,000 daltons, 800,000 daltons, 850,000 daltons, 900,000 daltons,950,000 daltons, 1,000,000 daltons, 2,000,000 daltons, 3,000,000daltons, 4,000,000 daltons, 5,000,000 daltons, 7,000,000 daltons,10,000,000 daltons.

In certain embodiments, the total concentration of polyethylene oxidefor use in the composition is in the range of 5 to 99.9% w/w, such asfrom 10 to 99.9% w/w, such as from 10 to 98% w/w, such as from 20 to 98%w/w, such as from 30 to 98% w/w, such as from 40 to 98% w/w, such asfrom 50 to 98% w/w, such as from 60 to 98% w/w, such as from 70 to 98%w/w, calculated as w/w % of the composition.

In particular embodiments, the level of polyethylene oxide 200,000daltons to achieve the desired viscosity as described herein may be atleast 1,020 mg, for polyethylene oxide 300,000 daltons it is at least544 mg, for polyethylene oxide 400,000 daltons it is at least 435 mg,for polyethylene oxide 600,000 daltons it is at least 324 mg, forpolyethylene oxide 900,000 daltons it is at least 243 mg, forpolyethylene oxide 1,000,000 daltons it is at least 203 mg forpolyethylene oxide 2,000,000 daltons and 4,000,000 daltons it is atleast 162 mg and for polyethylene oxide 5,000,000 daltons, 7,000,000daltons and 10,000,000 daltons it is at least 122 mg.

In some embodiments, the upper level of polyethylene oxide 200,000 to10,000,000 daltons to achieve the desired viscosity in pharmaceuticalcompositions described herein is approximately 1,100 mg.

The compositions as described herein may comprise mixtures ofpolyethylene oxides with different average molecular weights, forexample, in order to obtain polyethylene oxides with a desirable averagemolecular weight. Thus, in some embodiments, the pharmaceuticalcomprises different polyethylene oxide materials with different averagemolecular weights.

In certain embodiments, in order to obtain polyethylene oxide with adesirable average molecular weight, it is important to note that, insuch cases, it is necessary to use polyethylene oxides, which have anaverage molecular weight closest to the desired molecular weight toensure a narrow chain length distribution. In certain such embodiments,for example, equal amounts of polyethylene oxide 200,000 daltons andpolyethylene oxide 600,000 daltons may be mixed to obtain polyethyleneoxide 400,000 daltons.

A composition as described herein may comprise more than one differentkind of polyethylene oxide, such as 2, for example 3, such as 4, forexample 5, such as more than 5 different polyethylene oxides. In certainsuch embodiments, the composition comprises 1 to 4 differentpolyethylene oxides. In one such embodiment, the composition comprises 1to 3 different polyethylene oxides. In another such embodiment, thecomposition comprises 2 different polyethylene oxides.

The polyethylene oxide used in compositions according to the presentdescription may have a melting point higher than the body temperature ofthe individual (e.g., a human) in which the pharmaceutical compositionis to be used. Thus, in particular embodiments, the polyethylene oxidesemployed in the pharmaceutical compositions described herein may have amelting point of in the range of 38° C. to 200° C., such as in the rangeof 38° C. to 150° C., for example in the range of 38° C. to 120° C.,such as in the range of 38° C. to 100° C., for example in the range of65° C. to 100° C.

Plasticizer

A composition as described herein may also comprise at least oneplasticizer.

In particular embodiments, the composition comprises a poloxamer.

A composition as described herein may comprise more than one differentkind of plasticizer, such as 2, for example 3, such as more than 3different plasticizers. In certain such embodiments, the compositioncomprises 1 to 3 different plasticizers. In one such embodiment, thecomposition comprises 2 different plasticizers. In another suchembodiment, the different kind of plasticizer is a different kind ofpoloxamer.

In one embodiment, the composition comprises one or more plasticizers,preferably one or more plasticizers selected from the group consistingof poloxamers, such as poloxamer 188 and/or poloxamer 407.

In some embodiments, the composition comprises at least one poloxamer.Poloxamers may be copolymers or block copolymers and are a range ofnon-ionic surfactants of polyethylene glycol (PEG) and polypropyleneglycol (PPG).

The poloxamer may be Diol EO/PO block copolymers, which, for example, inchemical abstracts are described under the scientific namehydroxy-hydroxypoly (oxyethylene)poly(oxypropylene)-poly(oxyethylene)-block copolymer in combination withthe CAS register number. In specific embodiments, a suitable poloxamerfor use in a composition of the disclosure has a HLB value of at leastabout 18 such as, for example, at least approximately 20, preferably atleast 24. In certain embodiments, the average molecular weight of asuitable poloxamer is typically at least about 2,000 daltons.

Block copolymers of ethylene oxide and propylene oxide that may beincluded in the composition described herein have a molecular weight ofat least 2,000 daltons, typically in the range of 3,000 to 30,000daltons, such as in the range of 4,000 to 15,000 daltons.

Exemplary poloxamers that may be used in the compositions disclosedherein have the formula HO(C₂H₄O)a(C₃H₆O)_(b)(C₂H₄O)_(a)H, where “a” isan integer from 10 to 150, such as from 30 to 140, for example from 50to 100, such as from 65 to 90, for example from 70 to 90, and “b” is aninteger from 10 to 80, such as from 15 to 80, for example from 20 to 60,such as from 25 to 55.

Other plasticizers may be incorporated in the composition of thepharmaceutical compositions as described herein. A suitable plasticizermay be selected from mono- and di-acetylated monoglycerides,diacetylated monoglycerides, acetylated hydrogenated cottonseedglyceride, glyceryl cocoate, polyethylene glycols (for example with amolecular weight below 35,000 daltons) or polyethylene oxides (forexample with a molecular weight of about 35,000 to 600,000 daltons),dipropylene glycol salicylate glycerin, fatty acids and esters,phthalate esters, phosphate esters, amides, diocyl phthalate, phthalylglycolate, mineral oils, hydrogenated vegetable oils, vegetable oils,acetylated hydrogenated soybean oil glycerides, castor oil, acetyltributyl citrate, acetyl triethyl citrate, methyl abietate,nitrobenzene, carbon disulfide, beta-naphtyl salicylate, sorbitol,sorbitol glyceryl tricitrate, fatty alcohols, cetostearyl alcohol, cetylalcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol, sucroseoctaacetate, alfa-tocopheryl polyethylene glycol succinate (TPGS),tocopheryl derivative, diacetylated monoglycerides, diethylene glycolmonostearate, ethylene glycol monostearate, glyceryl monooleate,glyceryl monostearate, propylene glycol monostearate, macrogol esters,macrogol stearate 400, macrogol stearate 2,000, polyoxyethylene 50stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols,nonoxinols, octocinols, tyloxapol, poloxamers, polyvinyl alcohols,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65,polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitansesquioleate, sorbitan trioleate, sorbitan tristearate and sucroseesters, amyl oleate, butyl oleate, butyl stearate, diethylene glycolmonolaurate, glycerol tributyrate, Cumar W-1, Cumar MH-1, Cumar V-1,Flexol B-400, monomeric polyethylene ester, Piccolastic A-5, PiccalasticA-25, Beckolin, Clorafin 40, acetyl tributyl citrate, acetyl triethylcitrate, benzyl benzoate, butoxyethyl stearate, butyl and glycol estersof fatty acids, butyl diglycol carbonate, butyl ricinoleate, butylphthalyl butyl glycolate, camphor, dibutyl sebacate, dibutyl tartrate,diphenyl oxide, glycerine, HB-40, hydrogenated methyl ester of rosin,methoxyethyl oleate, monoamylphthalate, Nevillac 10, Paracril 26,technical hydroabietyl alcohol, Methylene glycol dipelargonate, solidaliphatic alcohols, and mixtures thereof.

In particular embodiments, the composition comprises cetostearylalcohol, castor oil, dibutyl sebacate, polyethylene oxides and/orpoloxamer as plasticizer. In another embodiment, the compositioncomprises polyethylene glycols,cetostearyl alcohol, cetyl alcohol,stearyl alcohol, alfa-tocopheryl polyethylene glycol succinate (TPGS),tocopheryl derivative, diacetylated monoglycerides, diethylene glycolmonostearate, ethylene glycol monostearate, glyceryl monooleate,glyceryl monostearate, propylene glycol monostearate, macrogol esters,macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50stearate, macrogol ethers, poloxamers, polysorbate 40, polysorbate 60,polysorbate 65, polysorbate 80, polysorbate 85, acetyl tributyl citrateand/or acetyl triethyl citrate as plasticizer. However, in otherembodiments, other plasticizers may also be used to provide desiredmaterial properties.

In certain embodiments, the amount of plasticizer in the composition isin the range of from 0 to 60% w/w, for example in the range of 0 to 50%w/w, such as in the range of 0 to 40% w/w, for example in the range of 0to 30% w/w, such as in the range of 0 to 20% w/w. In some embodiments,the amount of plasticizer in the composition is at least 1% w/w, forexample at least 5% w/w, such as for example at least 10% w/w. In someembodiments, the amount of plasticizer in the matrix composition is atthe most 20% w/w, such as in the range of 0 to 20% w/w, for example 5 to20% w/w, such as in the range of 10 to 20% w/w, for example 15 to 20%w/w. In other embodiments the amount of plasticizer in the matrixcomposition is at least 5% w/w, such as in the range of 5 to 25% w/w,for example 5 to 15% w/w, such as in the range of 5 to 10% w/w.

In some embodiments, the plasticizer is a poloxamer. In certain suchembodiments, the amount of poloxamer in the composition is at the most20% w/w, such as in the range of 0 to 20% w/w, for example 5 to 20% w/w,such as in the range of 10 to 20% w/w, for example 15 to 20% w/w. Inother embodiments, the amount of poloxamer in the composition is atleast 5% w/w, such as in the range of 5 to 25% w/w, for example 5 to 15%w/w, such as in the range of 5 to 10% w/w.

In particular such embodiments, the composition comprises one or moreplasticizer(s) and one or more polymer(s).

Active Drug Substance

An active drug substance suitable for use in the pharmaceuticalcompositions described herein is a therapeutically, prophylacticallyand/or diagnostically active drug substance (herein also abbreviated as“active substance” or “active drug substance”).

Examples of specific active drug substances suitable for use in thepharmaceutical compositions provided herein include:

Anti-inflammatory and antirheumatic active drug substances, such as, forexample: butylpyrazolidines, phenylbutazone, mofebutazone,oxyphenbutazone, clofezone, kebuzone, acetic acid derivatives andrelated substances, indometacin, sulindac, tolmetin, zomepirac,diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac,acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac,aceclofenac, bufexamac, oxicams, piroxicam, tenoxicam, droxicam,lornoxicam, meloxicam, methotrexate, propionic acid derivatives,ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen,suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid,oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen,dexketoprofen, fenamates, mefenamic acid, tolfenamic acid, flufenamicacid, meclofenamic acid, coxibs, celecoxib, rofecoxib, valdecoxib,parecoxib, etoricoxib, lumiracoxib, nabumetone, niflumic acid,azapropazone, glucosamine, benzydamine, glucosaminoglycan polysulfate,proquazone, orgotein, nimesulide, feprazone, diacerein, morniflumate,tenidap, oxaceprol, chondroitin sulfate, feprazone, dipyrocetyl,acetylsalicylic acid, quinolines, oxycinchophen, gold preparations,sodium aurothiomalate, sodium aurotiosulfate, auranofin,aurothioglucose, aurotioprol, penicillamine and bucillamine;

Analgesics, such as, for example: opioids, natural opium alkaloids,morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine,diamorphine, tapentadol, papaveretum, codeine, phenylpiperidinederivatives, ketobemidone, pethidine, fentanyl, diphenylpropylaminederivatives, dextromoramide, piritramide, dextropropoxyphene,bezitramide, methadone, benzomorphan derivatives, pentazocine,phenazocine, oripavine derivatives, buprenorphine, morphinanderivatives, butorphanol, nalbuphine, tilidine, tramadol, dezocine,salicylic acid and derivatives, acetylsalicylic acid, aloxiprin, cholinesalicylate, sodium salicylate, salicylamide, salsalate, ethenzamide,morpholine salicylate, dipyrocetyl, benorilate, diflunisal, potassiumsalicylate, guacetisal, carbasalate calcium, imidazole salicylate,pyrazolones, phenazone, metamizole sodium, aminophenazone,propyphenazone, nifenazone, anilides, paracetamol, phenacetin, bucetin,propacetamol, other analgesics and antipyretics, such as, for example:rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine,ziconotide;

Anaesthetics, such as, for example: ethers, diethyl ether, vinyl ether,halogenated hydrocarbons, halothane, chloroform, methoxyflurane,enflurane, trichloroethylene, isoflurane, desflurane, sevoflurane,barbiturates, methohexital, hexobarbital, thiopental, narcobarbital,opioid anaesthetics, fentanyl, alfentanil, sufentanil, phenoperidine,anileridine, remifentanil, other general anaesthetics, such as, forexample: droperidol, ketamine, propanidid, alfaxalone, etomidate,propofol, hydroxybutyric acid, nitrous oxide, esketamine, xenon, estersof aminobenzoic acid, metabutethamine, procaine, tetracaine,chloroprocaine, benzocaine, amides, bupivacaine, lidocaine, mepivacaine,prilocaine, butanilicaine, cinchocaine, etidocaine, articaine,ropivacaine, levobupivacaine, esters of benzoic acid, cocaine, otherlocal anaesthetics, such as, for example: ethyl chloride, dyclonine,phenol, capsaicin;

Antimigraine active drug substances, such as, for example: ergotalkaloids, dihydroergotamine, ergotamine, methysergide, lisuride,corticosteroid derivatives, flumedroxone, selective serotonin (5HT1)agonists, sumatriptan, naratriptan, zolmitriptan, rizatriptan,almotriptan, eletriptan, frovatriptan, other antimigraine preparations,pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone;

Antiepileptic active drug substances, such as, for example:barbituratesand derivatives, methylphenobarbital, phenobarbital, primidone,barbexaclone, metharbital, hydantoin derivatives, ethotoin, phenytoin,amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin,oxazolidine derivatives, paramethadione, trimethadione, ethadione,succinimide derivatives, ethosuximide, phensuximide, mesuximide,benzodiazepine derivatives, clonazepam, carboxamide derivatives,carbamazepine, oxcarbazepine, rufinamide, fatty acid derivatives,valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide,tiagabine, other antiepileptics, such as, for example: sultiame,phenacemide, lamotrigine, felbamate, topiramate, gabapentin,pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol,lacosamide, beclamide;

Anticholinergic active drug substances, such as, for example: tertiaryamines, trihexyphenidyl, biperiden, metixene, procyclidine, profenamine,dexetimide, phenglutarimide, mazaticol, bornaprine, tropatepine, etherschemically close to antihistamines, etanautine, orphenadrine (chloride),ethers of tropine or tropine derivatives, benzatropine, etybenzatropine;

Dopaminergic active drug substances, such as, for example: dopa and dopaderivatives, levodopa, melevodopa, etilevodopa, adamantane derivatives,amantadine, dopamine agonists, bromocriptine, pergolide,dihydroergocryptine mesylate, ropinirole, pramipexole, cabergoline,apomorphine, piribedil, rotigotine, monoamine, oxidase B inhibitors,selegiline, rasagiline, other dopaminergic agents, such as, for example:tolcapone, entacapone, budipine;

Antipsychotic active drug substances, such as, for example:phenothiazines with aliphatic side-chain, chlorpromazine,levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine,chlorproethazine, phenothiazines with piperazine structure, dixyrazine,fluphenazine, perphenazine, prochlorperazine, thiopropazate,trifluoperazine, acetophenazine, thioproperazine, butaperazine,perazine, phenothiazines with piperidine structure, periciazine,thioridazine, mesoridazine, pipotiazine, butyrophenone derivatives,haloperidol, trifluperidol, melperone, moperone, pipamperone,bromperidol, benperidol, droperidol, fluanisone, indole derivatives,oxypertine, molindone, sertindole, ziprasidone, thioxanthenederivatives, flupentixol, clopenthixol, chlorprothixene, tiotixene,zuclopenthixol, diphenylbutylpiperidine derivatives, fluspirilene,pimozide, penfluridol, diazepines, oxazepines, thiazepines, loxapine,clozapine, olanzapine, quetiapine, neuroleptics, tetrabenazine,benzamides, sulpiride, sultopride, tiapride, remoxipride, amisulpride,veralipride, levosulpiride, lithium, other antipsychotics, such as, forexample prothipendyl, risperidone, clotiapine, mosapramine, zotepine,aripiprazole, paliperidone;

Anxiolytic active drug substances, such as, for example: benzodiazepinederivatives, diazepam, chlordiazepoxide, medazepam, oxazepam, potassiumclorazepate, lorazepam, adinazolam, bromazepam, clobazam, ketazolam,prazepam, alprazolam, halazepam, pinazepam, camazepam, nordazepam,fludiazepam, ethyl loflazepate, etizolam, clotiazepam, cloxazolam,tofisopam, diphenylmethane derivatives, hydroxyzine, captodiame,carbamates, meprobamate, emylcamate, mebutamate,dibenzo-bicyclo-octadiene derivatives, benzoctamine, azaspirodecanedionederivatives, buspirone, other anxiolytics, such as, for example:mephenoxalone, gedocarnil, etifoxine;

Hypnotic and sedative active drug substances, such as, for example:barbiturates, pentobarbital, amobarbital, butobarbital, barbital,aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital,cyclobarbital, heptabarbital, reposal, methohexital, hexobarbital,thiopental, etallobarbital, allobarbital, proxibarbal, aldehydes andderivatives, chloral hydrate, chloralodol, acetylglycinamide chloralhydrate, dichloralphenazone, paraldehyde, benzodiazepineemeproniumderivatives, flurazepam, nitrazepam, flunitrazepam, estazolam,triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam,loprazolam, doxefazepam, cinolazepam, piperidinedione derivatives,glutethimide, methyprylon, pyrithyldione, benzodiazepine related drugs,zopiclone, zolpidem, zaleplon, ramelteon, other hypnotics and sedatives,such as, for example: methaqualone, clomethiazole, bromisoval,carbromal, scopolamine, propiomazine, triclofos, ethchlorvynol,valerian, hexapropymate, bromides, apronal, valnoctamide,methylpentynol, niaprazine, melatonin, dexmedetomidine,dipiperonylaminoethanol;

Antidepressant active drug substances, such as, for example:non-selective monoamine reuptake inhibitors, desipramine, imipramine,imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine,dibenzepin, amitriptyline, nortriptyline, protriptyline, doxepin,iprindole, melitracen, butriptyline, dosulepin, amoxapine, dimetacrine,amineptine, maprotiline, quinupramine, selective serotonin reuptakeinhibitors, zimeldine, fluoxetine, citalopram, paroxetine, sertraline,alaproclate, fluvoxamine, etoperidone, escitalopram, monoamine oxidaseinhibitors, isocarboxazid, nialamide, phenelzine, tranylcypromine,iproniazide, iproclozide, monoamine oxidase A inhibitors, moclobemide,toloxatone, other antidepressants, such as, for example: oxitriptan,tryptophan, mianserin, nomifensine, trazodone, nefazodone, minaprine,bifemelane, viloxazine, oxaflozane, mirtazapine, medifoxamine,tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone,duloxetine, agomelatine, desvenlafaxine, centrally actingsympathomimetics, such as, for example: amfetamine, dexamfetamine,lisdexamfetamine, metamfetamine, methylphenidate, dexmethylphenidate,pemoline, fencamfamin, modafinil, fenozolone, atomoxetine, fenetylline,xanthine derivatives, caffeine, propentofylline, other psychostimulantsand nootropics, such as, for example meclofenoxate, pyritinol,piracetam, deanol, fipexide, citicoline, oxiracetam, pirisudanol,linopirdine, nizofenone, aniracetam, acetylcarnitine, idebenone,prolintane, pipradrol, pramiracetam, adrafinil, vinpocetine;

Anti-dementia active drug subtances, such as, for example:anticholinesterases, tacrine, donepezil, rivastigmine, galantamine,other anti-dementia drugs, memantine, and ginkgo biloba;

Other nervous system active drug substances, such as, for example:parasympathomimetics, anticholinesterases, neostigmine, pyridostigmine,distigmine, ambenonium, choline esters, carbachol, bethanechol, otherparasympathomimetics, such as, for example: pilocarpine, cholinealfoscerate;

Active drug substances used in addictive disorders, such as, forexample: nicotine, bupropion, varenicline, disulfiram, calciumcarbimide, acamprosate, naltrexone, buprenorphine, methadone,levacetylmethadol, lofexidine, betahistine, cinnarizine, flunarizine,acetylleucine, gangliosides and ganglioside derivatives, tirilazad,riluzole, xaliproden, hydroxybutyric acid, amifampridine;

Opium alkaloids and derivatives, such as, for example: ethylmorphine,hydrocodone, codeine, opium alkaloids with morphine, normethadone,noscapine, pholcodine, dextromethorphan, thebacon, dimemorfan,acetyldihydrocodeine, benzonatate, benproperine, clobutinol, isoaminile,pentoxyverine, oxolamine, oxeladin, clofedanol, pipazetate, bibenzoniumbromide, butamirate, fedrilate, zipeprol, dibunate, droxypropine,prenoxdiazine, dropropizine, cloperastine, meprotixol, piperidione,tipepidine, morclofone, nepinalone, levodropropizine, dimethoxanate.

In certain embodiments, the active drug substance may, for example, bean active drug substance with abuse potential that presents a safetyrisk. Such active drug substance may, for example, be selected from:

1-(1-phenylcyclohexyl)pyrrolidine,1-(2-phenylethyl)-4-phenyl-4-acetoxypiperidine,1-[1-(2-thienyl)-cyclohexylpiperidine,1-[1-(2-thienyl)cyclohexyl]pyrrolidine,1-methyl-4-phenyl-4-propionoxy-piperidine, 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, 2,5-dimethoxy-4-ethylamphetamine,2,5-dimethoxyamphetamine, 2C-B-(4-bromo-2,5-dimethoxypenethylamine),2C-D (2,5-dimethoxy-4-methylphenethylamine), 2C-I(4-iodo-2,5-dimethoxy-phenethylamine), 2C-T-2(2,5-dimethoxy-4-ethylthiophenethylamine), 2C-T-4(2,5-dimethoxy-4-isopropyl thiophenethylamine), 2C-T-7(2,5-dimethoxy-4-(n)-propylthiopenethylamine),3,4-methylene-dioxymethamphetamine, 3,4,5-trimethoxyamphetamine,3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-N-ethylamphetamine,3-methylfentanyl, 3-methylthiofentanyl,4-bromo-2,5-dimethoxyamphetamine, 4-bromo-2,5-dimethoxyphenethylamine,4-methoxyamphetamine, 4-methyl-2,5-dimethoxyamphetamine,4-methylaminorex (cis isomer), 5-MeO-DIPT(5-methoxy-N,N-diisopropyltryptamine), 5-MeO-DMT(5-methoxy-N,N-dimethyltryptamine),5-methoxy-3,4-methylenedioxyamphetamine, acetorphin, acetorphine,acetyl-alpha-methylfentanyl, acetyl-alpha-methylfentanyl,acetyldihydrocodeine, acetylmethadol, acetylmethadol, alfentanil,allobarbital, allylprodin, allylprodine, alphacetylmethadol exceptlevo-alphacetylmethadol, alpha-ethyltryptamine, aphameprodine,alphamethadol, alphamethadol, alpha-methylfentanyl,alpha-methylthiofentanyl, alphaprodine, alprazolam, amfepramon,amfetaminil, amineptin, aminorex, amobarbital, amphetamine,dextroamphetamine, amylnitrit (all isomers of the amyl group), anabolicsteroids, anileridine, aprobarbital, barbital, barbituric acidderivative, BDB (3,4-methylenedioxyphenyl)-2-butanamine), benzethidin,benzethidine, benzoylecgonine, benzphetamine, benzphetamine,benzylmethylketon, benzylmorphine, betacetylmethadol,beta-hydroxy-3-methylfentanyl, beta-hydroxyfentanyl, betameprodine,betameprodine, betamethadol, betaprodine, bezitramide, bezitramide,boldenone, brolamfetamin, bromazepam, brotizolam, bufotenine,buprenorphine, butabarbital, butalbital, butobarbital, butorphanol, BZP(A 2)(1-benzylpiperazin), camazepam, cannabis, carfentanil, cathaedulis, cathine, cathinone, chloral betaine, chloral hydrate,chlordiazepoxide, chlorhexadol, chlorotestosterone (same as clostebol),chlorphentermine, clobazam, clonazepam, clonitazene, clonitazene,clorazepate, clortermine, clostebol, clotiazepam, cloxazolam, cocaleaves, cocaine, codeine, codeine & isoquinoline alkaloid, codeinemethylbromide, codeine-N-oxide, codoxim, cyclobarbital (hexemal NFN),cyprenorphine, dehydrochlormethyltestosterone, delorazepam,desomorphine, dexamfetamine, dexfenfluramine, dexmethylphenidate,dextromoramide, dextropropoxyphene, diacetylmorphine, diampromide,diazepam, dichloralphenazone, diethylpropion, diethylthiambutene,diethyltryptamine, difenoxin, dihydrocodeine, dihydroetorphine,dihydromorphine, dihydrotestosterone, dimenoxadol, dimepheptanol,dimethylthiambutene, dimethyltryptamine, dioxaphetyl butyrate,diphenoxylate, dipipanone, diprenorphine, dronabinol, drostanolone,drotebanol, ecgonine, estazolam, ethchlorvynol, ethinamate, ethylloflazepate, ethylestrenol, ethylmethylthiambutene, ethylmorphine,ethylmorphine, eticyclidin, etilamfetamine, etonitazene, etorphine,etoxeridine, etryptamine, fencamfamin, fenethylline, fenetylline,fenfluramine, fenproporex, fentanyl, fludiazepam, flunitrazepam,fluoxymesterone, flurazepam, formebolone, fungi and spores of thesepcies psilocype semilanceata, furethidine, gammahydroxybutanic acid,glutethimide, halazepam, haloxazolam, heroine, hydrocodone, hydrocodone& isoquinoline alkaloid, hydromorphinol, hydromorphone,hydroxypethidine, ibogaine, isobutylnitrit, isomethadone, ketamine,ketazolam, ketobemidone, levamfetamine, levo-alphacetylmethadol,levo-methamphetamine, levomethorphan, levomoramide, levophenacylmorphan,levorphanol, lisdexamfetamin, loprazolam, lorazepam, lormetazepam,lysergic acid, lysergic acid amide, lysergic acid diethylamide,marijuana, mazindol, MBDN(N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine), mCPP(1-(3-chlorphenyl)piperazine), mebutamate, mecloqualone, medazepam,mefenorex, MeOPP (1-(4-methoxyphenyl)piperazine), meperidine, meperidineintermediate, meprobamate, mescaline, mesocarb, mesterolone,metamfetamine, metazocine, methadone, methadone intermediate,methamphetamine, methandienone, methandranone, methandriol,methandrostenolone, methaqualone, methcathinone, methenolone,methohexital, methyldesorphine, methyldihydromorphine, methylphenidate,methylphenobarbital (mephobarbital), methyltestosterone, methyprylone,metopone, mibolerone, midazolam, modafinil, moramide-intermediate,morpheridine, morphine, morphine methylbromide, morphinemethylsulfonate, morphine-N-oxide, myrophine, N,N-dimethylamphetamine,nabilone, nalorphine, nandrolone, N-ethyl-1-phenylcyclohexylamine,N-ethyl-3-piperidyl benzilate, N-ethylamphetamine,N-hydroxy-3,4-methylenedioxyamphetamine, nicocodeine, nicocodine,nicodicodine, nicomorphine, nimetazepam, nitrazepam,N-methyl-3-piperidyl benzilate, noracymethadol, norcodeine, nordiazepam,norethandrolone, norlevorphanol, normethadone, normorphine, norpipanone,norpipanone, opium, oxandrolone, oxazepam, oxazolam, oxycodone,oxymesterone, oxymetholone, oxymorphone, para-fluorofentanyl, parahexyl,paraldehyde, pemoline, pentazocine, pentobarbital, petrichloral, peyote,phenadoxone, phenampromide, phenazocine, phencyclidine, phendimetrazine,phenmetrazine, phenobarbital, phenomorphan, phenoperidine, phentermine,phenylacetone, pholcodine, piminodine, pinazepam, pipradrole,piritramide, PMMA (paramethyxymethyl amphetamine), prazepam,proheptazine, properidine, propiram, psilocybine, psilocyn,pyrovalerone, quazepam, pacemethorphane, racemoramide, racemorphane,remifentanil, salvia divinorum, salvinorin A, secobarbital,secobarbital, sibutramine, SPA, stanolone, stanozolol, sufentanil,sulfondiethylmethane, sulfonethylmethane, sulfonmethane, talbutal,temazepam, tenamfetamin, testolactone, testosterone,tetrahydrocannabinols, tetrazepam, TFMPP(1-(3-triflourmethylphenyl)piperazine), thebacon, thebaine, thiamylal,thiofentanyl, thiopental, tiletamine & zolazepam in combination,tilidine, trenbolone, triazolam, trimeperidine, vinbarbital, zaleplon,zipeprol, zolpidem and zopiclon.

Other suitable examples of active drug substances suitable for use inthe pharmaceutical compositions described herein include, for example,alfentanil, allylprodine, alphaprodine, aniloridine, benzylmorphine,bezitramide, buprenorphine, butophanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diapromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, dextropropoxyphene, ketobemidone, levallorphan,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, morphine 6-glucuronide,morphine 3-glucuronide, myrophine, nalbuphine, narccine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,opium, oxycodone, oxycodeine, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, thebaine,levo-alphacetylmethadol (LAAM), remifentanil, carfentanyl, ohmefentanyl,MPPP, prodine, PEPAP, levomethorphan, etorphine, lefetamine, loperamide,diphenoxylate or pethidine.

Even further examples of active drug substances suitable for use in thepharmaceutical compositions described herein include anabolic steroids,cannabis, cocaine and diazepam.

In one embodiment, the active drug substance is selected from the groupconsisting of the therapeutic classes including non-steroidalanti-inflammatory substances and antirheumatic active drug substances.

In other embodiments, the active drug substance is selected fromtherapeutic classes including analgesics, opioids, antipyretics,anaesthetics, antimigraine agents, antiepileptics, anti-parkinsonagents, dopaminergic agents, antipsychotics, anxiolytics, sedatives,antidepressants, psychostimulants agents, dopamine, noradrenaline,nicotinic, alfa-andrenergic, serotonin, H3 antagonists used for ADHD andnootropics agents used in addictive disorders.

In still further embodiments, the active drug substance is selected fromtherapeutic classes including anaesthetics, centrally-acting analgesics,sedative-hypnotics, anxiolytics, appetite suppressants, decongestants,antitussives, antihistamines, antiemetics, antidiarrheals, and drugsused to treat narcolepsy and attention deficit hyperactivity disorder.

In certain embodiments, the active drug substance is associated withabuse syndromes and the active drug substance may, for example, beselected from opioids, CNS depressants, CNS stimulants, cannabinoids,nicotine-like compounds, glutamate antagonists and N-methyl-D-aspartate(NMDA) antagonists.

In specific embodiments, the active drug substance is an analgesic.Examples of analgesics suitable for use in the pharmaceuticalcompositions described herein include, for example, opioids, naturalopium alkaloids, morphine, opium, hydromorphone, nicomorphine,oxycodone, dihydrocodeine, diamorphine, tapentadol, papaveretum,codeine, phenylpiperidine derivatives, ketobemidone, pethidine,fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide,dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives,pentazocine, phenazocine, oripavine derivatives, buprenorphine,morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol,dezocine, salicylic acid and derivatives, acetylsalicylic acid,aloxiprin, choline salicylate, sodium salicylate, salicylamide,salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,diflunisal, potassium salicylate, guacetisal, carbasalate calcium,imidazole salicylate, pyrazolones, phenazone, metamizole sodium,aminophenazone, propyphenazone, nifenazone, anilides, paracetamol,phenacetin, bucetin, propacetamol, other analgesics and antipyreticssuch as, for example, rimazolium, glafenine, floctafenine, viminol,nefopam, flupirtine, ziconotide.

In certain such embodiments, the active drug substance is an opioid.Where an opioid is included as an active drug substance, the opioid maybe selected from naturally occurring opioids, synthetic opioids andsemisynthetic opioids.

In another embodiment, the active drug substance is selected fromamfetamine, dexamfetamine, lisdexamfetamine, metamfetamine,methylphenidate, dexmethylphenidate and combinations thereof.

In some embodiments, the pharmaceutical compositions disclosed hereinincludes an opioid, the opioid is selected from buprenorphine, codeine,dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone,morphine, pentazocine, oxycodeine, oxycodone, oxymorphone,norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol,tapentadol and dihydromorphine.

Where an opioid is used as an active drug substance, the opioid may bepresent in any of its crystalline, polymorphous, semi-crystalline, andamorphous or polyamorphous forms. Furthermore, in some embodiments, anopioid used as an active drug substance may be present in one or moreforms selected from its crystalline, polymorphous, semi-crystalline, andamorphous or polyamorphous forms.

Specific embodiments of the pharmaceutical compositions disclosed hereininclude an opioid as an active drug substance, the active drug substanceis selected from morphine, oxycodone, hydrocodone, hydromorphone,norhydrocodone, oxymorphone, noroxycodone, morphine-6-glucuronode andpharmaceutically acceptable salts of any of the aforementioned, such asfrom the group consisting of oxycodone hydrochloride, hydrocodonebitartrate, hydromorphone hydrochloride and morphine sulphatepentahydrate.

In certain embodiments, the pharmaceutical compositions as describedherein are suitable for use for water soluble as well as slightlysoluble or insoluble active drug substances.

In some embodiments, all of the above mentioned active drug substancesmay also be in the form of pharmaceutically acceptable salts, unchargedor charged molecules, molecular complexes, solvates, or anhydratesthereof, and, if relevant, isomers, enantiomers, racemic mixtures, andmixtures thereof.

In particular embodiments, the pharmaceutical compositions describedherein may comprise pharmaceutically acceptable salts of any of theabove mentioned active drug substances.

The term “pharmaceutically acceptable salts” of an active drug substanceincludes alkali metal salts such as, for example, sodium or potassiumsalts, alkaline earth metal salts such as, for example, calcium andmagnesium salts, and salts with organic or inorganic acid such as, forexample, hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, citric acid, formic acid, maleic acid, succinicacid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc.

The term “pharmaceutically acceptable salts” of an opioid includesalkali metal salts such as, for example, sodium or potassium salts,alkaline earth metal salts such as, for example, calcium and magnesiumsalts, and salts with organic or inorganic acids such as, for examplehydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, citric acid, formic acid, maleic acid, succinic acid,tartaric acid, methansulphonic acid, toluenesulphonic acid etc ortartrate acid. In particular embodiments, pharmaceutically acceptableopioid salts may be selected from the group consisting of sulphatesalts, hydrochloride salts and bitartrate salts.

The term “solvates” includes hydrates or solvates wherein other solvatesthan water are involved such as, for example, organic solvents likechloroform and the like.

Furthermore, in some embodiments, the active drug substance may be inany of its crystalline, polymorphous, semi-crystalline, amorphous orpolyamorphous forms and mixtures thereof.

The concentration of the active drug substance in the pharmaceuticalcomposition for use according to the disclosure depends on the specificactive drug substance, the disease to be treated, the condition of thepatient, the age and gender of the patient etc. The above-mentionedactive drug substances may be known active drug substances and a personskilled in the art will be able to find information as to the dosage ofeach active drug substance and, accordingly, will know how to determinethe amount of each active drug substance in the pharmaceuticalcomposition.

The active drug substance may be a new chemical entity for which theamount of information is limited. In such cases, the dosage has to beevaluated based on available preclinical and/or clinical data.

In some embodiments, the active drug substance is typically present inthe composition in an amount of from 5 to about 90% w/w such as, forexample, from about 5 to about 80% w/w, from about 5 to about 70% w/w,from about 5 to about 60% w/w, from about 5 to about 50% w/w, from about5 to about 40% w/w, from about 5 to about 30% w/w, from about 5 to about20% w/w, from about 5 to about 10% w/w.

In certain embodiments, when the active drug substance is an opioid,such as, for example, morphine, oxycodone, hydromorphone or oxymorphoneor pharmaceutically acceptable salts thereof, then said opioid istypically present in the compositions in a concentration of in the rangeof 5 to 70% w/w, for example in the range of 5 to 60% w/w, such as inthe range of 5 to 50% w/w, for example in the range of 5 to 45% w/w,such as in the range of 5 to 40% w/w, for example in the range of 5 to35% w/w, such as in the range of 5 to 30% w/w, for example in the rangeof 5 to 25% w/w, such as in the range of 5 to 20% w/w, for example inthe range of 5 to 15% w/w, such as in the range of 5 to 10% w/w.

In certain embodiments, the active drug substance is typically presentin the composition in an amount of from 1 to about 90% w/w such as, forexample, from about 1 to about 80% w/w, from about 1 to about 70% w/w,from about 1 to about 60% w/w, from about 1 to about 50% w/w, from about1 to about 40% w/w, from about 1 to about 30% w/w, from about 1 to about20% w/w, from about 1 to about 10% w/w.

In certain embodiments, when the active drug substance is an opioid,such as, for example, morphine, oxycodone, hydromorphone or oxymorphoneor pharmaceutically acceptable salts thereof, then said opioid istypically present in the compositions in a concentration of in the rangeof 1 to 70% w/w, for example in the range of 1 to 60% w/w, such as inthe range of 1 to 50% w/w, for example in the range of 1 to 45% w/w,such as in the range of 1 to 40% w/w, for example in the range of 1 to35% w/w, such as in the range of 1 to 30% w/w, for example in the rangeof 1 to 25% w/w, such as in the range of 1 to 20% w/w, for example inthe range of 1 to 15% w/w, such as in the range of 1 to 10% w/w.

In certain embodiments, the compositions comprise a load of the activedrug substance, such as an opioid. A load is generally less than 50% w/wof the active drug substance. For example, in certain such embodiments,the compositions may include an active drug substance in an amountselected from less than 40% w/w and less than 30% w/w.

In some embodiments, a pharmaceutical composition as described hereinmay comprise one active drug substance or more than one different activedrug substances. Typically, the amount of the active drug substancecorresponds to a daily or part of a daily therapeutic dose.

In certain embodiments, the pharmaceutical composition provides foradministration 1-6 times a day, normally 1-4 times daily, such as 1-3times daily, such as 1-2 times daily or 1 time daily.

In one embodiment, the pharmaceutical composition provides fortwice-daily administration. In another embodiment, the pharmaceuticalcomposition provides for once-daily administration.

Pharmaceutically Acceptable Excipients

The pharmaceutical compositions described herein may also contain otherexcipients in order to achieve one or more desired properties, such as,for example, better stability of the active drug substance or thepharmaceutical composition itself, enhance the abuse-deterrentproperties, loading of the active drug substance or deliverycharacteristics, such as release rate or release profile of an activedrug substance. Further, in some embodiments, the compositions describedherein may include excipients that facilitate manufacture and productionof dosage forms such as, for example, tablets suitable foradministration to individuals in need thereof.

In certain embodiments, a suitable pharmaceutically acceptable excipientfor use in compositions according to the present description may beselected from fillers, diluents, disintegrants, glidants, pH-adjustingagents, viscosity adjusting agents, solubility increasing or decreasingagents, osmotically active agents and solvents.

In some embodiments, suitable excipients include conventional tablet orcapsule excipients. These excipients may be, for example, diluents suchas dicalcium phosphate, calcium sulfate, lactose or sucrose or otherdisaccharides, cellulose, cellulose derivatives, kaolin, mannitol, drystarch, glucose or other monosaccharides, dextrin or otherpolysaccharides, sorbitol, inositol or mixtures thereof; binders such asalginic acid, calcium alginate, sodium alginate, starch, gelatin,saccharides (including glucose, sucrose, dextrose and lactose),carboxymethylcellulose, methylcellulose, veegum, larch arabolactan,polyethylene glycols, ethylcellulose, water, alcohols, waxes,polyvinylpyrrolidone such as PVP K90 or mixtures thereof; lubricantssuch as talc, silicium dioxide, magnesium stearate, calcium stearate,stearic acid, hydrogenated vegetable oils, sodium benzoate, sodiumchloride, leucine, carbowax 4000, magnesium lauryl sulfate, Sodiumlaurilsulfate, Stearyl alcohol, Polysorbate 20, Polysorbate 60,Polysorbate 80, Macrogol stearate, Macrogol lauryl ether, Stearoylmacrogolglycerides, Sorbitan stearate, Sorbitan laurate, Macrogolglycerol hydroxystearat, colloidal silicon dioxide and mixtures thereof,disintegrants such as starches, clays, cellulose derivatives includingcrosscarmellose, gums, aligns, various combinations ofhydrogencarbonates with weak acids (e.g., sodiumhydrogencarbonate/tartaric acid or citric acid) crosprovidone, sodiumstarch glycolate, agar, cation exchange resins, citrus pulp, veegum,glycollate, natural sponge, bentonite, sucralfate, calciumhydroxyl-apatite or mixtures thereof.

In certain embodiments, in addition to a polymer of a polyethyleneoxide, the composition may comprise an additional polymer such aspolyglycols selected from substantially water soluble, thermoplastic,crystalline, semi-crystalline or amorphous or a mixture of substantiallywater soluble, crystalline, semi-crystalline or amorphous polymers. Inparticular, in certain embodiments, the polyglycol is at leastthermoplastic. Suitable polyglycols for use in the composition include,for example, polyethylene glycols (for example with a molecular weightbelow 35,000 daltons), as well as derivatives of polyethylene glycol,such as mono or dimethoxypolyethylene glycols (mPEGs), polyethyleneoxides and/or block copolymers of ethylene oxide and propylene oxide.

In some embodiments, in addition to a polymer of a polyethylene oxide,the composition may comprise an additional polymer, such as, forexample, at least one polymer selected from: modified or unmodifiedwater soluble natural polymers such as glucomannan, galactan, glucan,polygalacturonic acid, polyxylane, polygalactomannans,rhanogalacturonan, polyxyloglycan, arabinogalactan, and starch,cellulose, chitosan, alginate, fibrin, collagen, gelatin, hyaluronicacid, amylopectin, pectin including low methylated or methoxylatedpectins, dextran and fatty acids and alcohols; synthetic polymers suchas Carbopol, carbomer, carbomer homopolymer, carboxyvinyl polymer,polyvinylpyrrolidone (PVP), PVA, PVB, Eudragit L methyl ester, EudragitL, Eudragit RL, Eudragit RS, Eudragit E, Eudragit S, PHPV, PHA, PCL,PLGA and PLA; and hydrogels made from the polymers or combined polymersmentioned above and or from polymers originated from HEMA, HEEMA, MEMA,MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA,PEGDA, and PEGDMA.

In certain embodiments, the composition as described herein may compriseone or more gelling agents. Examples are polymers selected from thegroup consisting of modified or unmodified water soluble naturalpolymers such as glucomannan, galactan, glucan, polygalacturonic acid,polyxylane, polygalactomannans, polyxyloglycan, arabinogalactan, starch,cellulose, chitosan, alginate, fibrin, collagen, gelatin, amylopectin,pectin including low methylated or methoxylated pectins, dextran;synthetic polymers such as PVA and PVB; and hydrogels made from thepolymers or combined polymers mentioned above and or from polymersoriginated from: HEMA, HEEMA, MEMA, MEEMA, EDGMA, NVP, VAc, AA,acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and/or PEGDMA,hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose,ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate or other cellulose derivates,carboxymethylcellulose sodium, carboxymethylcellulose calcium,carrageenans, guar gum, gellan gum, xanthan gum, tragacanth, and arabicgum.

In some embodiments, exemplary stabilizers (chemical) include TPG, forexample, in the form of TPGS (Vitamin E Polyethylene glycol succinate)and BHT, BHA, t-butyl hydroquinone, butylhydroxy toluene, calciumascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodiumbisulfite, sodium metabisulfite, tocopherol and derivates thereof,citric acid, tartaric acid, and ascorbic acid. Other stabilisers includetrivalent phosphorous, such as, for example, phosphite, phenolicantioxidants, hydroxylamines, lactones such as substitutedbenzofuranones, hindered phenols, thiosynergists and/or hindered amines,acids (ascorbic acid, erythorbic acid, etidronic acid, hypophosphorousacid, nordihydroguaiaretic acid, propionic acid etc.), phenols, dodecylgallate, octyl gallate, 1,3,5-trihydroxybenzene, organic and inorganicsalts (calcium ascorbate, sodium ascorbate, sodium bisulphite, sodiummetabisulfite, sodium sulfite, potassium bisulphite, potassiummetabisulphite), esters (calcium ascorbate, dilauryl thiodipropionate,dimyristyl thiodipropionate, distearyl thiodipropionate), pyranon(maltol), and vitamin E (tocopherol, D-[alpha]-tocopherol,DL-[alpha]-tocopherol, tocopheryl acetate, d-[alpha]-tocopheryl acetate,dl-[alpha]-tocopheryl acetate. However, other anti-oxidative agentsknown in the art may also be used. Other suitable stabilizers may beselected from, for example, sorbitol glyceryl tricitrate, and sucroseoctaacetate.

In one embodiment, a composition as described herein comprises one ormore stabilizers selected from above mentioned group of stabilizers. Inone such embodiment, the composition comprises butylhydoxytoluene and/orTPGS as a stabilizer. In another such embodiment, the compositioncomprises gallic acid and/or ascorbic acid as a stabilizer.

In certain embodiments, a release modifier may be incorporated in acomposition as described herein. A suitable release modifier may beselected from fatty acids and esters, fatty alcohols, cetyl alcohol,stearyl alcohol, mineral oils, hydrogenated vegetable oils, vegetableoils, acetylated hydrogenated soybean oil glycerides, Castor oil,phosphate esters, amides, phthalate esters, glyceryl cocoate oleylalcohol, myristyl alcohol, sucrose octaacetate, diacetylatedmonoglycerides, diethylene glycol monostearate, ethylene glycolmonostearate, glyceryl monooleate, glyceryl monostearate, propyleneglycol monostearate, macrogol esters, macrogol stearate 400, macrogolstearate 2000, polyoxyethylene 50 stearate, macrogol ethers,cetomacrogol 1000, lauromacrogols, poloxamers, polyvinyl alcohols,sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate,sorbitan tristearate, ethylcellulose, cellulose acetate, cellulosepropionate, cellulose nitrate, cellulose derivative selected from thegroup consisting of methylcellulose, carboxymethylcellulose and saltsthereof, cellulose acetate phthalate, microcrystalline cellulose,ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose and hydroxymethylpropylcellulose, celluloseacetate, polylactic acid or polyglycolic acid and copolymers thereof,methacrylates, a co-polymer of methacrylate-galactomannan etc.,polyvinyl alcohols, glycerinated gelatine and cocoa butter.

In some embodiments, other suitable release modifiers may be selectedfrom inorganic acids, inorganic bases, inorganic salts, organic acids orbases and pharmaceutically acceptable salts thereof, saccharides,oligosaccharides, polysaccharides, polyethylene glycol derivatives andcellulose and cellulose derivatives.

Alternatively or additionally, in particular embodiments, a compositionaccording to the present description may include a pharmaceuticallyacceptable excipient selected from a mono-, di-, oligo, polycarboxylicacid or amino acids such as, for example, acetic acid, succinic acid,citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid,maleic acid, sorbic acid etc., aspartic acid or glutamic acid etc.

In some embodiments, suitable organic acids that may be included in thecompositions described herein include, for example, acetic acid/ethanoicacid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid,cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid,gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolicacid, glyoxylic acid, lactic acid, levulinic acid, malonic acid,mandelic acid, oxalic acid, oxamic acid, pimelic acid, or pyruvic acid.

In certain embodiments, suitable inorganic acids that may be included inthe compositions described herein include, for example, pyrophosphoric,glycerophosphoric, phosphoric such as ortho and meta phosphoric, boricacid, hydrochloric acid, or sulfuric acid.

In particular embodiments, examples of suitable inorganic compounds thatmay be included in the compositions described herein include, forexample, aluminium, calcium or kalium.

In particular embodiments, examples of organic bases that may beincluded in the compositions described herein include, for example,p-nitrophenol, succinimide, benzenesulfonamide,2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine,ethyleneamine tris (hydroxymethyl) aminomethane, hydroxylamine andderivates of amines, sodium citrate, aniline or hydrazine. Examples ofinorganic bases that may be included in the compositions describedherein include, for example, aluminium oxide such as, for example,aluminium oxide trihydrate, alumina, sodium hydroxide, potassiumhydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide orKOH.

In some embodiments, pharmaceutically acceptable salts of an organicacid that may be included in the compositions described herein include,for example, an alkali metal salt or an alkaline earth metal salt suchas, for example, sodium phosphate, sodium dihydrogenphosphate, disodiumhydrogenphosphate etc., potassium phosphate, potassiumdihydrogenphosphate, potassium hydrogenphosphate etc., calciumphosphate, dicalcium phosphate etc., sodium sulfate, potassium sulfate,calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate, potassium hydrogencarbonate, calcium carbonate, magnesiumcarbonate etc., sodium acetate, potassium acetate, calcium acetate,sodium succinate, potassium succinate, calcium succinate, sodiumcitrate, potassium citrate, calcium citrate, sodium tartrate, potassiumtartrate or calcium tartrate.

In certain embodiments, suitable inorganic salts for that may be used ina composition as described herein include, for example, sodium chloride,potassium chloride, calcium chloride or magnesium chloride.

In some embodiments, the composition may comprise at least onesaccharide. Where a saccharide is included in a composition as describedherein, the saccharide may be selected from, for example, glucose,ribose, arabinose, xylose, lyxose, xylol, allose, altrose, inosito,glucose, sorbitol, mannose, gulose, glycerol, idose, galactose, talose,mannitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol,sucrose, fructose, lactose, dextrin, dextran, amylase or xylan.

In certain embodiments, the composition may also comprise celluloseand/or cellulose derivatives selected from the group consisting ofmethylcellulose, carboxymethylcellulose and salts thereof,microcrystalline cellulose, ethylhydroxyethylcellulose, ethylcellulose,cellulose acetate, cellulose proprionate, cellulose nitrate, celluloseacetate phthalate, ethylmethylcellulose, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose and hydroxymethylpropylcellulose.

Furthermore, in particular embodiments, the compositions describedherein may comprise one or more agents selected from sweetening agents,flavouring agents and colouring agents in order to provide an elegantand palatable preparation. Examples include maltol, citric acid, watersoluble FD&C dyes and mixtures thereof with corresponding lakes anddirect compression sugars such as Di-Pac from Amstar. In addition,coloured dye migration inhibitors such as; tragacanth, acacia orattapulgite talc may be added. Specific examples include calciumcarbonate, 1,3,5-trihydroxybenzene, chromium-cobalt-aluminium oxide,ferric ferrocyanide, ferric oxide, Iron ammonium citrate, iron (III)oxide hydrated, iron oxides, carmine red, magnesium carbonate andtitanium dioxide.

Preparation

The pharmaceutical compositions of the disclosure may be produced byvarious methods which are either known per se in the pharmaceuticalindustry or which, for example, are used in the production ofpolymer-based materials, depending upon the desired embodiment and thematerials employed in the pharmaceutical composition in question. Thepharmaceutical compositions according to the present description may beproduced by methods that are relatively simple and inexpensive.

Suitable preparation methods for pharmaceutical compositions accordingto the present description include conventional tablet compression, hotmelt-processing and other methods of preparing pharmaceuticalcompositions. In certain embodiments, hot melt-processing technology andthe use of thermoplastic and thermosetting plastic polymers are able togive pharmaceutical compositions with low porosity, high viscosity andbreaking strengths, like properties such as for example plastic which isdifficult to tear down. In particular embodiments, a combination of oneor more of the aforementioned methods may be employed for use in thepreparation of pharmaceutical compositions disclosed herein.

In some embodiments, the pharmaceutical compositions described hereinare prepared by hot melt-processing. In one such embodiment, thepharmaceutical compositions are prepared by, for example, 1, 2 ormultiple component extrusion, molding, 1, 2 or multiple componentinjection molding. In another such embodiment, the pharmaceuticalcompositions are prepared by 1, 2 or multiple component injectionmolding.

In embodiments where a preparation is needed in order to make thepharmaceutical composition either before or after the above-mentionedpreparation steps, the preparation may also comprise separate steps,such as, for example, wet granulation, dry granulation, meltgranulation, pelletizing, curing, spray coating, electrostatic coating,dip coating or other forms of preparation methods.

In one embodiment, the pharmaceutical composition is prepared byconventional tablet compression.

In another embodiment, the pharmaceutical compositions are prepared byconventional tablet compression and hot melt processing.

Geometry

The pharmaceutical compositions according to the present description maybe formed as cylindrical compositions. In certain embodiments, thepharmaceutical compositions are formed as a cylindrical shape optionallywith one or two tapered end(s).

For purposes of the pharmaceutical compositions according to the presentdescription, the cylindrical shape may be any geometrical shape havingthe same cross section area throughout the length of the geometricalshape. Within the present context, cross sections are perpendicular tothe axis of the cylinder. By way of example, if the cylindrical shape iselongated then the cross sections are perpendicular to the longitudinalaxis. Preferably, the cylindrical shape is elongated. The cross sectionof a cylinder within the meaning of the present disclosure may have anytwo-dimensional shape, for example the cross section may be circular,oval, parabola, hyperbola, rectangular, triangular, otherwise angular,star shaped or an irregular shape. Accordingly, the cylindrical shapemay for example be an elliptic cylinder, a parabolic cylinder, ahyperbolic cylinder or a prism. A prism within the present context is acylinder whose cross-section is a polygon.

In some embodiments, the pharmaceutical composition according to thepresent description may have any common tablet shapes. Exemplary tabletshapes may include, for example, standard convex, standard convex bisectnot flush, standard convex quadrisect flush, standard convexstraight-through bisect, compound cup, convex with bevel, flat-facedplain, flat-faced bevel-edged, flat-faced bevel-edged bisect, flat-facedbevel-edged quadrisect, flat-faced radius-edged, lozenge, modified ball,core rod type (hole in center), capsule, modified capsule, oval, bullet,arrowhead, triangle, arc triangle, square, pillow (arc square),rectangle, modified rectangle, diamond, pentagon, hexagon, octagonnatural edge, heart, half moon and almond. A skilled person would knowthe various kinds of shape that a tablet may be formed in.

In a particular embodiment, the pharmaceutical composition is preparedfor oral intake, preferably for oral intake by swallowing. Accordingly,the size of the pharmaceutical composition may be in a range that allowsfor oral intake by swallowing.

Cosmetic Coat

In some embodiments, the pharmaceutical composition according to thepresent description may also contain a cosmetic coat that fully coversthe composition. In certain such embodiments, the cosmetic coat may beselected from the group consisting of taste-masking coats, coats withaqueous moisture barriers and/or oxidative barriers to improve thestability of the composition, and coat containing colouring agents,sweetening agents and/or flavouring agents in order to provide anelegant and palatable pharmaceutical composition and/or to easydistinguishable dose strengths.

It can be particularly useful to coat compositions having different dosestrengths or active drug substances with cosmetic coats of differentcolours so that the different actives and dose strengths are easilydistinguished.

In certain embodiments, the cosmetic coat contains an active drugsubstance.

Where provided, the cosmetic coat may, in particular embodiments, beeasily soluble in aqueous media in order to facilitate contact of thecomposition with the surrounding aqueous media rapidly afteradministration. In one such embodiment, the cosmetic coat is dissolvedwithin 30 minutes after immersed in aqueous media such as, for example,phosphate buffer solution pH 6.8.

Administration

The pharmaceutical composition according to the present description canbe designed for oral administration. For example, in certainembodiments, the pharmaceutical compositions may be produced as tablets,for oral intake by swallowing one or more intact tablets of thepharmaceutical composition.

A pharmaceutical composition as described herein may comprise one activedrug substance or more than one different active drug substance.

In certain embodiments, a pharmaceutical composition containing anactive drug substance according to the present description is typicallyformulated for oral administration. Due to the possibility ofcontrolling the release rate of the active drug substance, in particularembodiments, the pharmaceutical composition may be adapted for oraladministration 1-6 times a day, such as 1-4 times daily, including 1-3times, 1-2 times or twice or once daily.

In some embodiments, the pharmaceutical compositions according to thepresent description can be prepared for delivery of the desired dosageof active drug substance. In particular embodiments, the dosage may bedependent on the individual to whom the pharmaceutical composition asdescribed herein is being administered and the active drug substance.

In particular embodiments, the dosage for each administration, whereindosages are in the range of 1 to 1,000 mg, such as in the range of 5 to1,000 mg, for example in the range of 8 to 1,000 mg, such as in therange of 10 to 1,000 mg, for example in the range of 30 to 1,000 mg,such as in the range of 1 to 750 mg, for example in the range of 1 to500 mg, such as in the range of 1 to 250 mg of an active drug substance.In certain such embodiments, the dosage for each administration is in arange selected from 5 to 500 mg and 5 to 250 mg of an active drugsubstance.

In some embodiments, when the active drug substance included in thepharmaceutical compositions is an opioid, the dosage may be selectedfrom a range of 1 to 1000 mg, a range of 10 to 1000 mg, a range of 15 to1000 mg, a range of 20 to 1000 mg, a range of 30 to 1000 mg, a range of1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of15 to 500 mg, a range of 15 to 250 mg, a range of 20 to 500 mg, a rangeof 20 to 250 mg, a range of 30 to 500 mg, a range of 30 to 250 mg, arange of 10 to 200 mg, a range of 15 to 200 mg, a range of 20 to 200 mg,and a range of 30 to 200 mg of the opioid. In certain such embodiments,the pharmaceutical composition includes opioid or a pharmaceuticallyacceptable salt thereof as an active drug substance and the dosage isselected from 10, 15, 20, 30, 50, 60, 80, 100 or 200 mg. In certain suchembodiments, the pharmaceutical composition includes morphine as anactive drug substance and the dosage is selected from 10, 15, 20, 30,50, 60, 80, 90, 100, 120, 180 or 200 mg.

In another embodiment, when the active drug substance included in thepharmaceutical compositions is an opioid, the dosage may be selectedfrom a range of 1 to 1,000 mg, a range of 10 to 1,000 mg, a range of 1to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of10 to 250 mg, a range of 1 to 150 mg, a range of 10 to 150 mg, a rangeof 1 to 100 mg a range of 10 to 100 mg, a range of 1 to 80 mg and arange of 10 to 80 mg of the opioid. In certain such embodiments, thepharmaceutical composition includes opioids or a pharmaceuticallyacceptable salt thereof as an active drug substance and the dosage isselected from 10, 15, 20, 30, 40, 60 or 80 mg. In certain suchembodiments, the pharmaceutical composition includes hydrocodone as anactive drug substance and the dosage is selected from 10, 15, 20, 30,40, 60 or 80 mg. In another such embodiments, the pharmaceuticalcomposition includes oxycodone as an active drug substance and thedosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg.

In still another embodiment, when the active drug substance included inthe pharmaceutical compositions is an opioid, the dosage may be selectedfrom a range of 1 to 1,000 mg, a range of 8 to 1,000 mg, a range of 1 to500 mg, a range of 1 to 250 mg, a range of 8 to 500 mg, a range of 8 to250 mg a range of 1 to 100 mg, a range of 8 to 100 mg, a range oft to 75mg, a range of 8 to 75 mg, a range of 1 to 64 mg and a range of 8 to 64mg of the opioid. In certain such embodiments, the pharmaceuticalcomposition includes opioids or a pharmaceutically acceptable saltthereof as an active drug substance and the dosage is selected from 8,12, 16, 32 or 64 mg. In certain such embodiments, the pharmaceuticalcomposition includes hydromorphone as an active drug substance and thedosage is selected from 8, 12, 16, 32 or 64 mg.

In still another embodiment, when the active drug substance included inthe pharmaceutical compositions is an opioid, the dosage may be selectedfrom a range of 1 to 1,000 mg, a range of 5 to 1,000 mg, a range of 1 to500 mg, a range of 1 to 250 mg, a range of 5 to 500 mg, a range of 5 to250 mg a range of 1 to 100 mg, a range of 5 to 100 mg, a range of 1 to50 mg, a range of 5 to 50 mg, a range of 1 to 40 mg, and a range of 5 to40 mg of the opioid. In certain such embodiments, the pharmaceuticalcomposition includes opioids or a pharmaceutically acceptable saltthereof as an active drug substance and the dosage is selected from 5,7.5, 10, 15, 20, 30 or 40 mg. In certain such embodiments, thepharmaceutical composition includes oxymorphone as an active drugsubstance and the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40mg.

In particular embodiments, the above-mentioned dosages are relevant whenthe individual in need of treatment is a human being, such as an adulthuman being.

Individuals in Need of Treatment

In some embodiments, the pharmaceutical composition of the disclosure isprepared for administration to an individual in need thereof. In certainsuch embodiments, the individual may be a mammal, and in specificembodiments the individual is a human being.

In certain embodiments, the pharmaceutical composition is for treatmentof pain and accordingly, the individual in need of treatment is anindividual suffering from pain.

In certain embodiments, wherein the active drug substance is an opioid,then the pharmaceutical compositions are suitable for treatment ofmoderate to severe pain such as severe pain.

In some embodiments, examples of individuals, who may benefit fromtreatment with the pharmaceutical compositions according to thedisclosure, include, for example, the following:

The individual may be an individual suffering from chronic pain, such asmoderate to severe chronic pain;

The individual may be an individual suffering from cancer and thepharmaceutical composition may be useful for continuous treatment ofpain or even moderate to severe pain, such as severe pain in anindividual suffering from cancer;

The individual may also be an individual who has suffered a moderate tosevere injury;

The individual may be an individual suffering from pain associated withsurgical conditions, such as a pre-surgical individual (an individual inneed of surgery) or a post surgical individual (an individual who hasundergone surgery);

The individual may also be an individual suffering from or havingsuffered from a myocardial infarction, sickle cell crises, kidney stoneor severe back pain;

The individual may also be an individual suffering from degenerativepain, herniated disc pain, fibromyalgia, neuropathic pain and/ornociceptive pain; and

The individual may also be an individual suffering from arthritis, suchas arthritis osteo, arthritis rheumatoid, arthritis psoriatica and/orarthritis urica.

No Alcohol-Induced Dose Dumping

The pharmaceutical compositions according to the present description maybe formulated or configured to provide a reduced risk foralcohol-induced dose dumping.

In specific embodiments, the pharmaceutical compositions according tothe present description may be formulated or configured such that thepharmaceutical composition does not exhibit alcohol induceddose-dumping. In such embodiments, the composition exhibits a solubilityand/or active drug substance release rate in alcohol containing media(for example, ethanol containing media) that is lower than or equal tothe solubility and/or release rate in aqueous media that does notinclude alcohol (for example, water, phosphate buffer medium pH 6.8 ordilute hydrochloric acid). In some such embodiments, the polyethyleneoxide and excipients selected for use in the pharmaceutical compositionare provided in relative amounts that result in an unchanged or lowerdissolution rate and/or release rate of the active drug substance inalcohol containing media (for example, ethanol containing media) ascompared to the solubility and/or release rate exhibited in aqueousmedia that does not include alcohol (for example, water, phosphatebuffer medium pH 6.8 or dilute hydrochloric acid). In certain suchembodiments, the dissolution and/or release rate of the active drugsubstance from the pharmaceutical composition in alcohol containingmedia (for example, ethanol containing media) is at least 1.25 timeslower, such as at least 1.5 times lower, such as at least 2 times lower,such as at least 5 times, such as at least 10 times lower than thedissolution and/or release rate of the active drug substance in aqueousmedia that does not include alcohol (for example, water, phosphatebuffer medium pH 6.8, dilute hydrochloric acid, and the like).

More specifically, in some embodiments, the pharmaceutical compositionmay be formulated or configured to mitigate or prevent alcohol-induceddose dumping. In certain embodiments, the solubility or release rate ofthe composition is lower or substantially the same in alcohol than thatin water. In certain such embodiments, the solubility or release rate ofthe composition is equal or at least 1.25 times lower such as at least1.5 times lower; at least 2 times lower in alcohol than in water,notably 5 times or 10 times lower.

In particular embodiments, the pharmaceutical compositions according tothe present description may be configured or formulated to mitigate orprevent alcohol-induced dose dumping. In certain such embodiments, thepharmaceutical compositions are formulated such that the ratio (R₅₀)between t_(50%) w/w (40% v/v ethanol in medium 1) and t_(50%) w/w(medium 1) is 1 or more. t_(50%) w/w (medium 1) denotes the time ittakes to release 50% w/w of the active drug substance from thepharmaceutical composition in an in vitro dissolution test according toUSP 35, NF 30, (711), Apparatus 2, paddle employing water optionallybuffered to a specific pH as dissolution medium (medium 1), and t_(50%)w/w (40% v/v ethanol in medium 1) denotes the time it takes to release50% w/w of the active drug substance from the pharmaceutical compositionin an in vitro dissolution test according to USP 35, NF 30, (711),Apparatus 2, paddle employing 40% v/v ethanol in medium 1 as dissolutionmedium.

In certain embodiments, the ratio R₅₀ is at the most 3 or at the most 2.Notably, in certain such embodiments, the ratio R₅₀ provided by thepharmaceutical compositions described herein is from 1 to 1.5 such as,for example, from 1 to 1.4, from 1 to 1.3, from 1 to 1.2, from 1 to 1.1,from 1 to 1.05, about 1, from 1 to 0.95 or from 1 to 0.9.

In particular embodiments, the same may also apply for ratiosdetermined, for example, when 25%, 30%, 40%, 60%, 70%, 80%, 90% and/or95% w/w has been released, the conditions being as described above.

Abuse-Deterrent

The pharmaceutical compositions according to the present description areabuse-deterrent such that abuse administration is reduced, prevented oravoided. Abuse administration typically includes injection and/orsnorting.

Injection may be avoided by providing a non-injectable compositionhaving such high viscosity that injection is difficult or impossible,because a liquid solution cannot be obtained.

The term “non-injectable composition,” as used herein, refers topharmaceutical compositions having a viscosity of at least 95 mPa·s, forexample at least about 100 mPa·s, such as at least about 105 mPa·s, forexample at least about 110 mPa·s, such as at least about 120 mPa·s, forexample at least about 130 mPa·s, such as at least about 140 mPa·s, forexample at least about 150 mPa·s, such as at least about 160 mPa·s, forexample, at least about 170 mPa·s, such as at least about 180 mPa·s, forexample at least about 190 mPa·s, such as at least about 200 mPa·s. forexample at least about 220 mPa·s, such as at least about 240 mPa·s,where the viscosity is measured according to “Viscosity Test #2,”described in the “Viscosity test” disclosure. In particular embodiments,the term “non-injectable composition,” as used herein, refers topharmaceutical compositions having a viscosity of at least 170 mPa·s,where the viscosity is measured according to “Viscosity Test #2,”described in the “Viscosity test” disclosure.

Furthermore, the term “non-injectable composition,” as used herein, mayalso refer to pharmaceutical compositions having a viscosity in a rangeselected from between about 0.5 Pa·s to about 3,000 Pa·s, between about0.5 Pa·s to about 2,500 Pa·s, between about 0.5 Pa·s to about 2,000Pa·s, between about 0.5 Pa·s to about 1,700 Pa·s, between about 5 Pa·sto about 3,000 Pa·s, between about 10 Pa·s to about 3,000 Pa·s, betweenabout 20 Pa·s to about 3,000 Pa·s, between about 30 Pa·s to about 3,000Pa·s, between about 40 Pa·s to about 3,000 Pa·s, between about 45 Pa·sto about 3,000 Pa·s, between about 45 Pa·s to about 2,500 Pa·s, betweenabout 45 Pa·s to about 2,000 Pa·s, between about 45 Pa·s to about 1,700Pa·s, between about between about 46 Pa·s to about 1,700 Pa·s, where theviscosity is measured according to “Viscosity Test #1,” described in the“Viscosity test” disclosure. In particular embodiments, the term“non-injectable composition,” as used herein, refers to pharmaceuticalcompositions having a viscosity of at least about 46 Pa·s, where theviscosity is measured according to Viscosity Test #1, described in the“Viscosity test” disclosure.

Snorting may be avoided by providing a non-snortable composition, whichcannot be tampered into small particles or powder form such thatsnorting is made impossible.

In certain embodiments of the pharmaceutical compositions describedherein, the term “non-snortable composition” refers to compositionswherein at least 90 wt % of the particles obtained after physicaltampering of the composition is larger than about 1,050 μm, such aslarger than about 1,100 μm, such as larger than about 1,150 μm. Inparticular embodiments, the term “non-snortable composition,” as usedherein, refers to a composition where at least 90 wt % of the particlesobtained after physical tampering of the pharmaceutical composition islarger than 1,100 μm.

In certain circumstances, an abuser may tamper with pharmaceuticalcompositions in a manner or by using a method that achieves maximal sizereduction of the pharmaceutical composition in a minimal amount of time,while obtaining small particles, a powder, or other similar products,which can be dissolved or administered as easily as possible.

A series of abuse or tampering methods have been developed to illustratethe extent of the pharmaceutical compositions described herein of beingabuse-deterrent.

If a pharmaceutical composition disintegrates into particles, then itmay be possible to dissolve or suspend the particles and use them forabuse purposes. Moreover, if it is possible to disintegrate (e.g.,crush) a pharmaceutical composition, then it is possible to use thepowder for snorting or sniffing and, in this way, abuse the composition.However, if it is not possible to crush a pharmaceutical composition,then there will be no particles to use for such abuse purposes. Inparticular embodiments, the pharmaceutical compositions described hereincannot be crushed into particles by the apparatus (e.g., tablet hardnesstester) specified in Ph. Eur.

A particle size reduction test method has been developed to evaluateabuse potential when the pharmaceutical composition is subjected tophysical tampering.

In some embodiments, a pharmaceutical composition is abuse-deterrent,provided that the pharmaceutical composition does not change its releaseprofile from a controlled release to an immediate release of the activedrug substance subsequent to physical tampering (e.g., particle sizereduction test, where the test program is successfully completed), whichindicates that the pharmaceutical composition is abuse-deterrent. Insome such embodiments, tests on a pharmaceutical composition subjectedto physical tampering may also result in equipment failure, and in suchan instance, the test program is considered successfully completed,indicating a pharmaceutical composition as abuse-deterrent.

If a pharmaceutical composition is crushed or broken into small piecesor small particles, an increased exposed surface area is created, whichmay increase the release rate of the active drug substance. Such anincrease in release rate may lead to an increased potential for abuse.If a change in the release profile of the active drug substance from acontrolled release to an immediate release is noticed, thepharmaceutical composition is considered to have failed. At such apoint, the pharmaceutical composition is considered to have potentialfor abuse, such as by snorting or chemical extraction and it isevaluated. If the active drug substance can be extracted from thecompromised pharmaceutical composition, the ease with which suchextracted active drug substance can be injected is evaluated.

Crisping

The crisping test methods as described herein include methods intendedto circumvent the controlled release mechanism in or interfere with thecontrolled release profile of a pharmaceutical composition. Crisping isa heating process designed to remove, reduce, or degrade at least someof the unwanted or undesired excipients contained within a dosage formand make the dosage form easier to abuse the active drug substance.Crisping may be employed to make it easier to crush the composition intosmall particles or a powder form so that snorting is made possible, orto make it easier to dissolve the composition into an injectable liquidsolution, dispersion, or suspension.

Crisping or heating methods, such as, for example, heating in an oven, amicrowave oven, a spoon over an open flame, and the like, may beemployed by a potential abuser to it make it easier to reduce theparticle size and/or the viscosity of the pharmaceutical compositions.The heating is normally stopped when the pharmaceutical compositionstarts to turn a brown colour. Further processes designed to facilitateor enable abuse such as, for example, particle size reduction,extraction and/or injection are typically initiated after the crispingprocess is completed.

In certain embodiments, the pharmaceutical compositions according to thepresent description are not made easier to crush into snortableparticles or powder form or to dissolve into an injectable liquidsolution by crisping. In certain embodiments, stearate may be added tothe pharmaceutical composition as described herein to facilitate thecolour change of the composition to a brown and/or dark colour or evento facilitate the composition burning when exposed to a crispingprocess. In a particular embodiment, the stearate added is magnesiumstearate, calcium stearate and/or stearic acid.

Particle Size Reduction

The particle size reduction test methods described herein includemethods for reducing the particle size of the pharmaceuticalcompositions via physical tampering, such as, for example, crushing,hammering, chopping, grinding, grating, cutting, and other means ofparticle size reduction.

The particle size reduction test can be carried out using a number ofmechanical and electrical tools that are common household items or arereadily commercially available. Tools that may be used in carrying outparticle size reduction testing include, for example, a mortar andpestle, a hammer, a grater, a food chopper, a coffee grinder, and thelike.

Pharmaceutical compositions and dosage forms (including, for example,tablets), that have been subjected to physical tampering may be furtheranalyzed by use of image processing and/or particle size analysis.Pharmaceutical compositions subjected to physical tampering may beanalyzed by collecting the different fractions and analyzing, such as,for example, by weighing and/or dissolving to assess the contents ofactive drug substance in the different fractions and/or to assess thedissolution rate. For comparison, a control dissolution test asdescribed in the “Dissolution test” disclosure may be performed usingintact tablets (e.g., tablets that have not been subjected to physicaltampering), and the results from the control dissolution test may beused as control data.

Extraction

The extraction test methods described herein include methods forevaluating the extractability of active drug substance(s) frompharmaceutical compositions in different types of solvents. Theextraction test can be carried out using approximately 3 ml of water toprepare a solution of, for example, MS Contin® for injection.

Shaking

Different amount of solvents and ways of handling the solutions havebeen tested. In certain embodiments, in order to ensure that as much aspossible of the active drug substance has been extracted, shaking isselected as an extraction method. In certain such embodiments,extraction of an active drug substance from a pharmaceutical compositionmay be facilitated by placing a pharmaceutical composition in at leastone solvent and shaking the pharmaceutical composition and the at leastone solvent.

In particular embodiments, in order to ensure that as much as possibleof the active drug substance has been extracted, continuous shaking isselected as an extraction method. In one embodiment, extraction of anactive drug substane from a pharmaceutical composition may befacilitated by placing a pharmaceutical composition in at least onesolvent and continuously shaking the pharmaceutical composition and theat least one solvent. In some embodiments, “continuous shaking,” as usedherein, refers to shaking for at least 1 second, for at least 5 seconds,for at least 30 seconds, for at least 1 min, for at least 5 minutes, forat least 10 minutes, for at least 15 minutes, for at least 30 minutes,for at least 45 minutes, for at least 60 minutes, for at least 2 hours,for at least 4 hours, for at least 8 hours, for at least 12 hours, forat least 24 hours, for at least 2 days, for at least 3 days, for atleast 4 days, for at least 5 days, for at least 6 days, for at least 1week, for at least 2 weeks, for at least a month.

Unshaken/Undisturbed

In another embodiment, as an extraction method, the pharmaceuticalcomposition may be placed in at least one solvent and left unshakenand/or undisturbed for a period of time. In certain embodiments, thepharmaceutical composition may be placed in at least one solvent andleft unshaken and/or undisturbed for at least 4 hours, at least 8 hours,at least 12 hours, at least 24 hours, at least 48 hours, and at least 72hours. In certain such embodiments, the pharmaceutical composition maybe placed in at least one solvent and left unshaken and/or undisturbed,and the active drug substance in the solvent may be first measured afterat least 24 hours.

The amount of active drug substance in the solvent may be measured atselect time points within the first 60 minutes. In some embodiments, theamount of active drug substance in the solvent may be measured at leastone time, at least two times, at least three times, at least four times,at least five times, and at least six times, within the first 60 minutesof placing the pharmaceutical composition in the at least one solvent.In particular embodiments, the amount of active substance in the solventmay be measured at least one time, at least two times, at least threetimes, at least four times, at least five times, and at least six times,within the first 24 hours of placing the pharmaceutical composition inthe at least one solvent. In an embodiment, the amount of active drugsubstance in the solvent may be measured at at least three time pointswithin the first 60 minutes, so as to evaluate the rate at which theactive drug substance is released into the solvent.

Extraction of active drug substance from pharmaceutical compositions canbe performed by dissolving, for example, tablets in different types ofsolvents. In particular embodiments, the tablets in different solventsmay be shaken and/or continuous shaken. In other embodiments, thetablets in different solvents may be unshaken or undisturbed. Thesolvents can be chosen to cover a broad range of liquids with low andhigh pH, with some being some polar and some non-polar. In certainembodiments, the solvents may be categorized into five groups: such asfor example, aqueous solutions, such as, for example, solution pH 1.2;buffer pH 6.8; buffer pH 10.0; water; and water+ethanol (40% v/v);beverages, such as, for example; Coca-Cola®; quinine containing softdrinks, such as, for example; tonic water and bitter lemon; Coca-Cola®+ethanol (40% v/v); and vodka; common household liquids, such as, forexample, 1% acetic acid; ethanol; methylethylketone; and acetone.

In some embodiments, it has been shown to be difficult to extract activesubstances from the pharmaceutical composition described herein insolvents such as beverages. In certain such embodiments, it has beenshown to be difficult to extract active substances from thepharmaceutical composition described herein in solvents such ascarbonated and/or soft drinks, including Coca-Cola®, and the like.

Injection

The injection test methods described herein include methods forevaluating the abuse potential of active drug substance frompharmaceutical compositions both quantitatively (i.e., such as, forexample, time, yield, and unit operations required) and qualitatively(i.e., such as, for example, appearance).

In some embodiments, the general strategy behind the injection testmethods, as described herein, is to mimic the actual procedures appliedby drug abusers when preparing a pharmaceutical composition forinjection and injecting it. In some such embodiments, the study designis therefore divided into three parts, such as, for example,preparation, filtration, and injection.

In certain embodiments, the objective is to record the time and effortrequired to prepare a solution or dispersion that can be used forinjection and the obtained yield of the active drug substance. Asdescribed herein, drug abusers are, typically, only prepared to spend alimited amount of time for preparing a pharmaceutical composition forabuse. In certain such embodiments, all of the tests disclosed hereincan be performed in an aqueous media, which is a commonly-used solventfor injection. Finally, the appearance of the resultingsolution/dispersion is assessed in order to evaluate the likelihood thata drug abuser would inject the resulting injectable mass.

In certain embodiments, the pharmaceutical compositions described hereinhave predominantly high viscous properties analogous to plastic. In anaqueous medium or in the gastrointestinal tract, the pharmaceuticalcompositions described herein transforms from having high viscousproperties to having predominately elastic properties that control therelease rate of active drug substance, and which resist rapid extractionand/or injection. In particular embodiments, the predominately elasticproperties of the pharmaceutical compositions in an aqueous medium or inthe gastrointestinal tract provides a controlled-release profile of theactive drug substance in an individual.

The high viscosity of the composition turns not only the compositioninto a non-injectable dispersion/gel, but also significantly delays thesolubility of the composition to completely form into a gelatinous mass.In some embodiments, the high viscosity of the composition turns notonly the composition into a non-injectable dispersion/gel, but alsosignificantly deters the abuse of the pharmaceutical composition byeluting at least one polymer from the composition into the solvent,which turns the solvent into a gelatinous mass. In some suchembodiments, the at least one polymer is a polyethylene oxide. Incertain embodiments, the average molecular weight of the at least onepolyethylene oxide eluting from the composition into the solvent is lessthan 5,000,000 daltons, for example less than 4,000,000 daltons, such asless than 3,000,000 daltons, for example less than 2,000,000 daltons,such as less than 1,000,000 daltons, for example less than 800,000daltons, such as less than 600,000 daltons, for example less than500,000 daltons.

In particular embodiments, the high viscosity of the composition is in arange selected from between about 0.5 Pa·s to about 3,000 Pa·s, betweenabout 0.5 Pa·s to about 2,500 Pa·s, between about 0.5 Pa·s to about2,000 Pa·s, between about 0.5 Pa·s to about 1,700 Pa·s, between about 5Pa·s to about 3,000 Pa·s, between about 10 Pa·s to about 3,000 Pa·s,between about 20 Pa·s to about 3,000 Pa·s, between about 30 Pa·s toabout 3,000 Pa·s, between about 40 Pa·s to about 3,000 Pa·s, betweenabout 45 Pa·s to about 3,000 Pa·s, between about 45 Pa·s to about 2,500Pa·s, between about 45 Pa·s to about 2,000 Pa·s, between about 45 Pa·sto about 1,700 Pa·s, between about between about 46 Pa·s to about 1,700Pa·s, where the viscosity is measured according to “Viscosity Test #1,”described in the “Viscosity test” disclosure. In a specific embodiment,the viscosity of the composition at least about 46 Pa·s, where theviscosity is measured according to Viscosity Test #1, described in the“Viscosity test” disclosure.

In certain embodiments, the high viscosity of the composition is atleast 95 mPa·s, for example at least about 100 mPa·s, such as at leastabout 105 mPa·s, for example at least about 110 mPa·s, such as at leastabout 120 mPa·s, for example at least about 130 mPa·s, such as at leastabout 140 mPa·s, for example at least about 150 mPa·s, such as at leastabout 160 mPa·s, for example, at least about 170 mPa·s, such as at leastabout 180 mPa·s, for example at least about 190 mPa·s, such as at leastabout 200 mPa·s. for example at least about 220 mPa·s, such as at leastabout 240 mPa·s, where the viscosity is measured according to “ViscosityTest #2,” described in the “Viscosity test” disclosure. In particularembodiments, the high viscosity of the composition is at least 170mPa·s, where the viscosity is measured according to “Viscosity Test #2,”described in the “Viscosity test” disclosure.

The high viscosity of the composition deters direct injection and alsoserves as a significant barrier to prevent volatilization (e.g.,inhalation) of the incorporated active drug substance at elevatedtemperature or snorting if the composition is crushed or broken intosmall pieces or small particles. In certain embodiments, the compositionresults in a highly viscous and/or unclear, opaque or cloudydispersion/gel upon contact with and/or immersion in an aqueous medium,which may form a strong adhesion to the nose and nasal tissue walls and,thereby, result in discomfort in the nasal cavity of the abuser.

In some embodiments, it has been shown to be difficult to inject theabuse-deterrent pharmaceutical composition when the viscosity of thecomposition is at least 46 Pa·s, where the viscosity is measuredaccording to Viscosity Test #1, described in the “Viscosity test”disclosure.

In certain embodiments, it has been shown to be difficult to inject theabuse-deterrent pharmaceutical composition when the viscosity of thecomposition is at least 100 mPa·s, where the viscosity is measuredaccording to “Viscosity Test #2,” described in the “Viscosity test”disclosure.

In some embodiments, the abuse-deterrent pharmaceutical compositions, asdescribed herein, may form a gel that resists passage or is difficult toinject through a needle.

In further embodiments, the abuse-deterrent pharmaceutical compositions,as described herein, may further include a viscosity increasing agent,such as, for example, a gelling agent, and the like.

EXAMPLES

Certain embodiments of the disclosure are further illustrated in thefollowing non-limiting examples.

Dissolution Test

Dissolution tests were performed in accordance with USP 35, NF 30,(711), Apparatus 2 (paddle method). The dissolution medium consistedeither of phosphate buffer solution pH 6.8 with/without ethanol or ofdilute hydrochloric acid with/without ethanol. The volume of thedissolution medium was 900 ml and the rotation speed of the paddles was50 rpm or 75 rpm throughout the dissolution run. Samples were withdrawnat suitable time intervals and analysed for content of active drugsubstance by means of UV-detector or HPLC with UV-detector.

Dissolution Test (Immediate Release)

For the immediate-release test, the dissolution medium consisted ofdilute hydrochloric acid. The volume of the dissolution medium was 900ml and the rotation speed of the paddles was 75 rpm throughout thedissolution run.

Dissolution Test (Controlled Release)

For the controlled-release test, the dissolution medium consisted ofphosphate buffer solution pH 6.8. The volume of the dissolution mediumwas 900 ml and the rotation speed of the paddles was 50 rpm throughoutthe dissolution run.

No Alcohol-Induced Dose Dumping Test

For the no alcohol-induced dose dumping test, the dissolution mediumconsisted of phosphate buffer solution pH 6.8 with/without 40% v/vethanol. The volume of the dissolution medium was 900 ml and therotation speed of the paddles was 50 rpm throughout the dissolution run.

Crisping Test

Three (3) whole tablets were placed in a 50 ml glass bottle. The bottlewas placed in the center of a microwave oven and heated for apredetermined amount of time (e.g., 8 and 16 minutes) at maximum effect(900 W). Afterwards, 9 ml of purified water was added to the bottle. Thebottle was placed on a flatbed laboratory shaker (IKA-Werke HS-501digital) and was shook continuously (speed 150/min) for 3 days atambient temperature to dissolve the tablets and to reduce clumping.

Viscosity Test

Four (4) tablets were weighed and placed in a bottle with 12 ml purifiedwater. The bottle was placed on a flatbed laboratory shaker (IKA-WerkeHS-501 digital) and was shook continuously (speed 150/min) for 3 days atambient temperature to dissolve the tablets and to reduce clumping.

Viscosity can be measured using a Brookfield RVDV-E viscometer(Brookfield Engineering, Middleboro, Mass. USA) with spindle number 15(0.5-1700 Pa·s), a 7R tube, a small sample adapter SC4-45Y and tested inthe range of 1, 5, 10 and 20 rpm, respectively, or with spindle number21 (0.05-170 Pa·s), a 13R tube, and a small sample adapter SC4-45Y at 20rpm. The temperature was controlled and in the range of 21-22° C.

Viscosity Test #1

In one viscosity test (Viscosity Test #1), the viscosity can be measuredusing a Brookfield RVDV-E viscometer (Brookfield Engineering,Middleboro, Mass. USA) with spindle number 15 (0.5-1700 Pa·s), a 7Rtube, and a small sample adapter SC4-45Y at 5 rpm. The temperature wascontrolled and in the range of 21-22° C.

Viscosity Test #2

In another viscosity test (Viscosity Test #2), the viscosity can bemeasured using a Brookfield RVDV-E viscometer (Brookfield Engineering,Middleboro, Mass. USA) with spindle number 21 (0.05-170 Pa·s), a 13Rtube, and a small sample adapter SC4-45Y at 20 rpm. The temperature wascontrolled and in the range of 21-22° C.

Particle Size Reduction Test

Particle size reduction of pharmaceutical compositions was tested usinga coffee grinder and/or a nutmeg grater. The methods described hereinare used to evaluate the efforts required to reduce the particle size ofthe pharmaceutical compositions via physical grinding or grating of thetablets.

Tablets were ground in either a Moulinex-1411 R coffee grinder withstainless steel blades (model: the original grinder; 50 g -180WAR100G31/6W0) at 10 000-20 000 rpm or a Krups F203 coffee grinder withstainless steel blades (Model: 75 g—200 W F2034210/6W0-1512 R) at 30000-50 000 rpm for 15 seconds or to no more particle size reduction orequipment failure and, afterwards, analyzed by use of Image Processing.A drawing of the coffee grinder chamber is shown in FIGS. 1 and 2.

Tablets were grated by using a nutmeg grater with a stainless steel starblade or a Microplane® grater with stainless steel zester grater or afine or spice blade for 1½ minutes. A drawing of the nutmeg grater withstainless steel star blade is shown in FIG. 3.

The samples were analyzed using an image processing setup comprising adigital SLR with RAW or TIFF capabilities (Canon EOS 350D, resolution3466×2306 (8MP) or Nikon D3100, resolution 4608×3272 (14.2MP)), a fixedlens (Canon EF 100 mm 1:2:8 USM Macro or Tamron 90 mm 1:2:8 Macro), astable camera stand, a suitable background for the particles (e.g., ablack paper square) and light (to avoid reflections) plus a calibratedlight microscopy scale bar from Leitz.

A sample was spread onto the black background, and the particles wereseparated. The position of the camera setup was adjusted and focusedsuch that entire sample was inside the approximate view-area for thecamera before pictures were taken.

Data were processed by using the software: RawTherapee 3.0.1.0(Conversion of RAW-files to uncompressed TIFF.), ImageJ 1.45b(Thresholding of TIFF images (binarization) and particle size measuring(data rendering)) and Microsoft Excel 2010 (data analysis).

Preparation of Pharmaceutical Compositions

A general method for the preparation of a pharmaceutical composition, asdisclosed herein, is described below.

An accurate amount of the polymer (i.e., in the examples below:polyethylene oxide) is loaded into a MTI mixer followed by an accurateamount of the active drug substance and/or plasticizer and/or otherpharmaceutically acceptable excipient(s), if any. The mixing isperformed at 900-2000 rpm and at a time period up to 20 min. At thestart of the mixing the temperature is about 19-21 ° C. and the finaltemperature of the mixture is about 30-50 ° C. The mixture is thenallowed to cool to room temperature and is ready to be fed into aninjection moulding machine. The injection moulding machine used is anArburg Allrounder 420 C 1000-60/60.

Example 1

Preparation of a Pharmaceutical Composition Containing PEO 400,000 forUse According to the Disclosure

A composition (batch No. 1577-051A) according to the disclosure wasprepared from the following ingredients:

Composition mg PEO 400,000 436.2 Poloxamer 188 116.3 Morphine Sulphate29.1 Pentahydrate

The composition was prepared as described above.

The composition was subjected to the dissolution test (controlledrelease) described above. The results are shown in FIG. 4 as the releaseof morphine (%) versus time (minutes) in phosphate buffer solution pH6.8. The release of morphine is shown for intact tablets and groundtablets (ground in a Moulinex-1411 R coffee grinder).

The viscosity of the composition was measured as described above. Theviscosity was found to be 93 Pa·s at 5 rpm (using Viscosity Test #1).

Particle size reduction of the composition was measured as describedabove. The average particle size was 0.706±1.63 mm and the five largestparticles were; 12.1 mm; 3.0 mm; 2.7 mm; 2.2 mm; and 1.9 mm. The resultsare shown in FIG. 5.

Example 2

Preparation of a Pharmaceutical Composition Containing PEO 600,000 forUse According to the Disclosure

A composition (batch No. 1577-051B) according to the disclosure wasprepared from the following ingredients:

Composition mg PEO 600,000 348 Poloxamer 188 93 Oxycodone HCl 23.25

The composition was prepared as described above.

The composition was subjected to the dissolution test (controlledrelease) described above. The results are shown in FIG. 6 as the releaseof oxycodone (%) versus time (minutes) in phosphate buffer solution pH6.8 with and without 40% v/v ethanol. The release of oxycodone is shownfor intact tablets and ground tablets (ground in a Moulinex-1411 Rcoffee grinder).

The viscosity of the composition was measured as described above. Theviscosity was found to be 74 Pa·s at 5 rpm (using Viscosity Test #1).

Particle size reduction of the composition was measured as describedabove. The average particle size was 0.455±0.639 mm and the five largestparticles were; 12.1 mm; 4.0 mm; 3.9 mm; 3.8 mm; and 3.7 mm. The resultsare shown in FIG. 7.

Example 3

Preparation of a Pharmaceutical Compositions Containing PEO 2,000,000for Use According to the Disclosure

A composition (batch No. 1581-065) according to the disclosure wasprepared from the following ingredients:

Composition mg PEO 2,000,000 188 Poloxamer 188 50.2 Hydromorphone HCl12.55

The composition was prepared as described above.

The composition was subjected to the dissolution test (controlledrelease) described above. The results are shown in FIG. 8 as the releaseof hydromorphone (%) versus time (minutes) in phosphate buffer solutionpH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411R coffee grinder).

The viscosity of the compositions was measured as described above. Theviscosity was found to be 46 Pa·s at 5 rpm (using Viscosity Test #1).

Particle size reduction of the composition was measured as describedabove. The average particle size was 0.495±0.643 mm and the five largestparticles were 10.5 mm; 3.6 mm; 3.6 mm; 3.5 mm; and 3.5 mm. The resultsare shown in FIG. 9.

Example 4

Preparation of a Pharmaceutical Composition Containing PEO 10,000,000According to the Disclosure

A composition (batch no. 1581-066) according to the disclosure wasprepared from the following ingredients:

Composition mg PEO 10,000,000 110 Poloxamer 188 80 Oxymorphone HCl 10

The composition was prepared as described above.

The composition was subjected to the dissolution test (controlledrelease) described above. The results are shown in FIG. 10 as therelease of oxymorphone (%) versus time (minutes) in phosphate buffersolution pH 6.8 for intact tablets and ground tablets (ground in aMoulinex-1411 R coffee grinder).

The viscosity of the composition was measured as described above. Theviscosity was found to be 79.6 Pa·s at 5 rpm (using Viscosity Test #1).

Particle size reduction of the composition was measured as describedabove. The average particle size was 0.547±0.640 mm and the five largestparticles were 5.8 mm; 4.8 mm; 4.7 mm; 4.7 mm; and 4.4 mm. The resultsare shown in FIG. 11.

Example 5

Oxycontin® OP 40 mg

Oxycontin® OP 40 mg was subjected to the dissolution test (controlledrelease) described above. The results are shown in FIG. 12 as therelease of oxycodone (%) versus time (minutes) in phosphate buffersolution pH 6.8 for intact tablets and ground tablets (ground in aMoulinex-1411 R coffee grinder).

The viscosity of Oxycontin® OP 40 mg was measured as described above.The viscosity was found to be 46 Pa·s at 5 rpm (using Viscosity Test#1).

Particle size reduction of Oxycontin® OP 40 mg was measured as describedabove. The average particle size was 0.341±0.301 mm and the five largestparticles were 3.0 mm; 2.7 mm; 2.7 mm; 2.6 mm; and 2.4 mm. The resultsare shown in FIG. 13.

Example 6

Preparation of Morphine Prolonged Release Pharmaceutical Composition forUse According to the Disclosure

A 200 mg morphine composition (batch No. 12-0060-067) according to thedisclosure was prepared from the following ingredients:

Composition Mg PEO 200 000 291.6 PEO 600 000 291.6 Morphine Sulphate197.2 Pentahydrate BHT 0.8

The composition was subjected to the no alcohol-induced dose dumpingtest described above. The results are shown in FIG. 14 as release ofmorphine (%) versus time (minutes) in phosphate buffer solution pH 6.8with/without 40% v/v ethanol. The release of morphine is shown forintact tablets.

Example 7

Crisping Test

A 60 mg morphine composition (batch No. 12-066-067) according to thedisclosure was prepared from the following ingredients:

Composition Mg PEO 200 000 354.3 PEO 600 000 354.3 Morphine Sulphate 60Pentahydrate BHT 0.8

The composition was subjected to the crisping test described above. Forcomparison, MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER 40 mg(containing hydroxypropyl methylcellulose (HPMC)) were subjected to thesame crisping test.

The composition of MST Continus® and the composition of MS Contin® areidentical. MST Continus® is the European trademark and MS Contin® is theAmerican trademark.

The results are shown in Table 1 below.

TABLE 1 Morphine MST Oxycontin ® Crisping composition 60 Continus ® OPOpana ® (minutes) mg 60 mg 80 mg ER 40 mg 0 Viscosity >240075 >2400 >2400 (mPas) Injectable No Yes No No Assay (%) 100 98 99 98 8Viscosity >2400 93 60 >2400 (mPas) Injectable No Yes Yes No Assay (%) 9999 99 98 16 Viscosity >2400 0 0 30 (mPas) Injectable No Yes Yes YesAssay (%) 97 96 73 99

Example 8

Test of Particle Size Reduction of Pharmaceutical Compositions by Use ofa Coffee Grinder

A 200 mg morphine composition (batch No. 2654-056) according to thedisclosure was prepared from the following ingredients:

Composition Mg PEO 200 000 291.6 PEO 600 000 291.6 Morphine Sulphate197.2 Pentahydrate BHT 0.8

The composition was subjected to the dissolution test (controlledrelease) described above. The results are shown in FIG. 15 as therelease of active substance (%) versus time (minutes) in phosphatebuffer solution pH 6.8. The release of active substance is shown forintact tablets and ground tablets (ground in a Krups F203 coffeegrinder). For comparison, MST Continus® 60 mg and Oxycontin® OP 40 mgwere subjected to the same test. The results are shown in FIG. 15.

Example 9

Test of Particle Size Reduction of Pharmaceutical Compositions by Use ofa Nutmeg Grater

A 200 mg morphine composition (batch No. 2654-056) according to thedisclosure was prepared from the following ingredients:

Composition Mg PEO 200 000 291.6 PEO 600 000 291.6 Morphine Sulphate197.2 Pentahydrate BHT 0.8

The composition was subjected to the dissolution test (immediaterelease) described above. The results are shown in FIG. 16 as therelease of active substance (%) versus time (minutes) in dilutehydrochloric acid. The release of active substance is shown for gratedtablets (Nutmeg grater). For comparison, MST Continus® 60 mg, Oxycontin®OP 80 mg and Opana® ER 40 mg were subjected to the same test. Theresults are shown in FIG. 16.

Particle size reduction of the composition was measured as describedabove. The average particle size was 1.94±2.57 mm and the five largestparticles were 21.4 mm; 15.1 mm; 12.8 mm; 8.7 mm; and 7.8 mm. Theresults are shown in FIG. 17.

For comparison, MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER40 mg were subjected to the same test. For MST Continue 60 mg, theaverage particle size was 0.410±0.250 mm and the five largest particleswere 4.9 mm; 4.7 mm; 4.1 mm; 3.7 mm; and 3.5 mm. For Oxycontin® OP 80mg, the average particle size was 0.596±0.337 mm and the five largestparticles were 5.9 mm; 5.0 mm; 4.3 mm; 3.4 mm; and 3.1 mm. For Opana® ER40 mg, the average particle size was 0.513±0.489 mm and the five largestparticles were 9.4 mm; 8.7 mm; 7.8 mm; 6.8 mm; and 6.4 mm. The resultsare shown in FIGS. 18-20.

The five largest particles were lumps; some were big lumps and also bigand flakey.

The dimensions of the tablets are shown in Table 2 below.

TABLE 2 Depth, mm Length, Height, Width, (convex Tablet mm mm mm tablet)Morphine composition 19.5 6.2 7.4 N/A 200 mg MST Continus ® 60 mg 7.254.5 7.25 N/A Oxycontin ® OP 80 mg 9.5 4.25 9.5 N/A Opona ® ER 40 mg 8.63.5 8.6 0.5

Example 10

Extraction Test

A 60 mg morphine composition (batch No. 12-066-067) according to thedisclosure was prepared from the following ingredients:

Composition Mg PEO 200 000 354.3 PEO 600 000 354.3 Morphine Sulphate 60Pentahydrate BHT 0.8

The composition was subjected to the extraction test described above.Two (2) tablets were placed in a 50 ml beaker, 10 ml solvent (purifiedwater or Coca-Cola®) was added, and the beaker was sealed withParafilm®. The beaker with tablets was left undisturbed at 25° C./60% RHfor 24 hours. The free solvent was poured into a tared empty beaker, theviscosity of the free solvent was measured by the viscosity test asdescribed above (Viscosity Test #2), and the active drug substancecontent in the free solvent (assay) was determined using HPLC withUV-detector.

By comparison, MST Continus® 60 mg, Oxycontin® OP 80 mg, and Opana® ER40 mg were subjected to the same extraction test.

The results of are shown in table 3 below.

TABLE 3 Free solvent Assay Viscosity In- Formulation (ml) (%) (mPa s)jectable Note Morphine composition 60 mg Water 5.8 30.8 >2400 No Tabletshape disappeared Coca- 3.2 24.4 >2400 No Partly dissolved Cola ® therest having a white core MST Continus ® 60 mg Water 9.3 87.9 0 YesIntact Spongy looking Coca- 8.8 92.9 0 Yes Intact Spongy Cola ® lookingOxycontin ® OP 80 mg Water 5.5 36.5 160 Yes Swollen transparent tabletsCoca- 5.5 48.4 68 Yes Swollen Cola ® transparent tablets Opana ® ER 40mg Water 5.0 50.1 73 Yes Swollen transparent tablets Coca- 4.6 45.8 105Yes Swollen Cola ® transparent tablets

1-21. (canceled)
 22. An abuse-deterrent tablet formulated for oraladministration of an opioid, the tablet consisting of a tabletcomposition and, optionally, a cosmetic coat, wherein: the tabletcomposition comprises: (a) about 1-60% w/w of the opioid; and (b) about40-98% w/w of a polyethylene oxide (PEO) selected from the groupconsisting of (i) a single PEO having an average molecular weight offrom about 400,000 daltons to about 900,000 daltons and (ii) two or morePEOs having a combined average molecular weight of from about 400,000daltons to about 900,000 daltons, wherein the cosmetic coat, whenpresent, covers at least a portion of the tablet composition, anddissolves within 30 minutes after contact with aqueous media, whereinthe tablet composition exhibits a viscosity of at least 170 mPas whenmeasured by Viscosity Test #2, or a viscosity of at least 46 Pas whenmeasured by Viscosity Test #1, such that the tablet composition, whensubjected to a liquid environment, forms a viscous hydrogel that resistspassage through a hypodermic needle.
 23. The abuse deterrent tablet ofclaim 22, wherein the opioid is selected from the group consisting ofbuprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl,hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine,oxycodone, oxymorphone, norhydrocodone, noroxycodone,morphine-6-glucuronode, tramadol, tapentadol, dihydromorphine, andpharmaceutically acceptable salts thereof.
 24. The abuse deterrenttablet of claim 22, wherein the opioid is selected from the groupconsisting of morphine and pharmaceutically acceptable salts thereof.25. The abuse deterrent tablet of claim 22, wherein the opioid comprisesmorphine sulfate.
 26. The abuse deterrent tablet of claim 22, whereinthe opioid is selected from the group consisting of oxycodone andpharmaceutically acceptable salts thereof.
 27. The abuse deterrenttablet of claim 22, wherein the opioid comprises oxycodonehydrochloride.
 28. The abuse deterrent tablet of claim 22, wherein theopioid is selected from the group consisting of hydrocodone andpharmaceutically acceptable salts thereof.
 29. The abuse deterrenttablet of claim 22, wherein the opioid comprises hydrocodone bitartrate.30. The abuse deterrent tablet of claim 22, wherein the tabletcomposition exhibits a release rate of opioid in phosphate bufferedsaline with 40% v/v ethanol that is equal to or lower than the releaserate of opioid in phosphate buffered saline.
 31. The abuse deterrenttablet of claim 22, wherein the tablet yields a non-snortablecomposition when subjected to physical tampering selected from crushing,hammering, grinding, grating, and cutting.
 32. The abuse deterrenttablet of claim 22, wherein the tablet composition comprises a singlePEO having an average molecular weight of from about 400,000 daltons toabout 600,000 daltons.
 33. The abuse deterrent tablet of claim 22,wherein the tablet composition comprises a single PEO having an averagemolecular weight of about 400,000 daltons.
 34. The abuse deterrenttablet of claim 22, wherein the tablet composition comprises a singlePEO having an average molecular weight of about 600,000 daltons.
 35. Theabuse deterrent tablet of claim 22, wherein the tablet compositioncomprises two or more PEOs having a combined average molecular weight offrom about 400,000 daltons to about 600,000 daltons.
 36. The abusedeterrent tablet of claim 22, wherein the tablet composition comprisestwo or more PEOs having a combined average molecular weight of about400,000 daltons.
 37. The abuse deterrent tablet of claim 22, wherein thetablet composition comprises two or more PEOs having a combined averagemolecular weight of about 600,000 daltons.
 38. The abuse deterrenttablet of claim 22, wherein the tablet composition comprises a first PEOhaving an average molecular weight of about 200,000 daltons and a secondPEO having an average molecular weight of about 600,000 daltons, whereinthe combined average molecular weight of the PEO present in the tabletcomposition is about 400,000 daltons.
 39. The abuse deterrent tablet ofclaim 22, further comprising at least 1% w/w of a plasticizer.
 40. Theabuse deterrent tablet of claim 39, wherein the plasticizer is selectedfrom the group consisting of poloxamers having an average molecularweight from about 3,000 to about 30,000 daltons.
 41. A method fortreating an individual suffering from moderate to severe pain, themethod comprising administering to the individual an abuse-deterrenttablet according to claim 22, wherein the tablet composition, whensubjected to a liquid environment, forms a viscous hydrogel that resistspassage through a hypodermic needle.
 42. The method of claim 41, whereinthe opioid is selected from morphine and pharmaceutically acceptablesalts thereof.
 43. The method of claim 41, wherein the opioid comprisesmorphine sulfate.
 44. The method of claim 41, wherein the opioid isselected from oxycodone and pharmaceutically acceptable salts thereof.45. The method of claim 41, wherein the opioid comprises oxycodonehydrochloride.
 46. The method of claim 41, wherein the opioid isselected from hydrocodone and pharmaceutically acceptable salts thereof.47. The method of claim 41, wherein the opioid comprises hydrocodonebitartrate.
 48. The method of claim 41, wherein the method comprisestwice daily administration.
 49. The method of claim 41, wherein themethod comprises once daily administration.